Zwitterionic polymers

ABSTRACT

Polymers may be made from zwitterionic monomers having controlled architectures and molecular weights, using living polymerisations such as group or atom transfer radical polymerisation. For instance polymers may be formed by atom transfer radical polymerisation using a copper chloride catalyst, a ligand which is water soluble, and a water soluble tertiary alkyl halide initiator to form homopolymers having controlled polydispersities of less than 1.5 and block copolymers with other hydrophilic or hydrophobic monomers. One suitable zwitterionic monomer is 2-methacryloyloxy-2′-trimethylammoniumethyl phosphate inner salt. The block copolymers may spontaneously form micelles, believed to have zwitterionic, for instance phosphorylcholine, groups at the external surface, which may be useful as drug delivery systems with improved biocompatibility.

[0001] The present inventions relates to zwitt rionic polymers havingcontrolled architectures, specifically having controlled chain lengthand/or block chain length in block copolymers.

[0002] It is known that phosphorylcholine based polymers can be used toproduce surfaces which are resistant to protein adsorption and blood andmicrobial cell adhesion. Copolymers of2-methacryloyloxymethyl-2′-trimethylammonium ethyl phosphate inner salt(MPC) formed by solution polymerisation using thermal initiators such asazoisobutyronitrile are described in WO-A-9301221. Comonomers areselected to confer particular surface binding characteristics. Forinstance hydrophobic comonomers such as C₈₋₂₄-alkyl(meth)acrylatecomonomers confer surface binding for hydrophobic surfaces. Reactivecomonomers confer crosslinkability or covalent reactivity to surfacefunctional groups. Ionic monomers confer electrostatic binding tooppositely charged surfaces. Various improvements have been described,for instance cationic comonomers have been used to provide additionaldesirable characteristics as described in WO-A-9822516. Improvedcrosslinking systems are described in WO-A-9830615.

[0003] The mixture of MPG and comonomers in the above specifications hasreactivity ratios far from 1:1. In thermal (or redox) initiated radicalpolymerisations, the rate of propagation is very high compared to therate of initiation. New initiator radicals are generated throughout thecourse of a polymerisation. Since one of the monomers is more reactivethan the other(s), the composition of monomer available forpolymerisation throughout a polymerisation process, and hence thecomposition of polymer molecules made throughout a process, varies.Whilst some compositional variation may be tolerated in someapplications, and may even have benefit in terms of properties itconferred, it is often desirable to provide polymer having a narrowerrange of composition and molecular weight.

[0004] Some improvements in the compositional variation have beendescribed in WO-A-9822516 and PCT/GB00/02078. The polymerisations wereconducted under monomer starved conditions, by feeding a mixture ofmonomers over an extended period into the reaction vessel containinginitiator. However these processes still produce polymers having a widevariation in terms of molecular weight (polydispersity).

[0005] Polymerisation methods for polymerising ethylenically unsaturatedmonomers to provide narrow polydispersities have been developed. Oneclass of polymerisations use ionic living polymers. These are generallyconducted in organic solvents (toluene, tetrahydrofuran) in whichzwitterionic monomers, which tend to be highly hydrophilic, areinsoluble. One type of living polymerisation, sometimes termedpseudo-living polymerisation, developed by Matyjaszewski is called atomtransfer radical polymerisation (ATRP). The process is described interalia in. WO-A-96/30421, U.S. Pat. No. 5,807,937, WO-A-98140415,WO-A-9807758 and U.S. Pat. No. 5,789,487. All these polymerisationsrequire a low stationary concentration of growing radicals, M_(n).,which are in a fast dynamic equilibrium with the dormant species,M_(n)X. This reduces the extent of termination reactions by two growingradicals joining together. The initiation reaction should be very fastcompared to the rate of propagation. The reaction of growing radicalsM_(n). react reversibly with radicals X which, in ATRP are atoms,generally halogen atoms. In ATRP, the reversible reaction involves atransition metal compound which is able to change oxidation states. Thegeneral reaction scheme of atom and group transfer may be represented asfollows:

[0006] in which InX is the initiator compound, M_(t) is the transitionmetal compound, which is convertabl from n oxidation state to the n+1oxidation state, and M is the monomer. Ki is the initiation rateconstant, and K_(p) is the propagation rate constant. The reactionsinvolving the transition metal redox cycle are reversible. The rateconstants of the various reactions result in relatively low stationarylevels of the moiety In—M_(n)., since this reacts to form the dormantspecies In—M—X. The molecular weight increases linearly with increasingmonomer conversion. In ATRP, ligands are generally present to complexthe transition metal ions, generally in both oxidation states.

[0007] Most of Matyjaszewski's ATRP reactions are conducted in organicsolvent. Recently X—S Wang et al., in Chem. Commun., 1999, 1817-1818 andin Polymer Preprint 2000, 41(1), 413-414, describe atom transfer radicalpolymerisations conducted in aqueous media involving water solubleethylenically unsaturated monomers such as hydroxy ethyl methacrylate(HEMA), sodium methacrylate, sodium 4-vinylbenzoate,2-aminoethylmethacrylate, 2-sulphatoethyl methacrylate ammonium salt,3-sulphopropyl methacrylate potassium salt, N-(4-vinylbenzyl) trimethylammonium chloride and monomethoxy-capped oligo(ethyleneoxide)methacrylate (OEGMA). The initiators used were water solublebromine substituted compounds such as the reaction product ofmonomethoxy-capped oligo(ethylene oxide) with 2-bromoisobutyryl bromide(OEGBr), 4-bromo-α-toluic acid or ethyl 2-bromopropanoic acid, or2-(N,N-dimethylamino) ethyl-2′-bromoisobutyrate. The reactions could beconducted at ambient temperatures, at which conversion rates of morethan 95% were obtained after less than half an hour. Block copolymerscould be formed by the use of the OEGMA-derived macro initiator forpolymerising 2-sulphatoethyl methacrylate. Armes describedpolymerisation of a carboxybetaine monomer in similar systems at aconference in Cambridge, “Controlled free radical polymerisation” Sep.21, 2000.

[0008] Haddleton, D. M. et al at 217th ACS National meeting, AnaheimMar. 21-25, 1999, POLY-024, described catalytic chain transf r (CCT)polymerisations in aqueous solutions of acrylic monomers, such as2-methacryloyloxy-2′-trimethylammonium ethyl phosphate, using a cobaltcatalyst, cobaloxine boron fluoride. In CCTP the metal of the catalystbecomes directly joined (reversibly) to the growing polymer chain.

[0009] According to the present invention there is provided a newpolymerisation process in which ethylenically unsaturated monomersincluding a zwitterionic monomer of the general formula I

Y B X  I

[0010] in which Y is an ethylenically unsaturated group selected fromH₂C═CR—CO—A—, H₂C═CR—C₆H₄—Al—, H₂C═CR—CH²⁹, R²O—CO—CR═CR—CO—O,RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

[0011] A is —O— or NR¹;

[0012] A¹ is selected from a bond, (CH₂)_(n) ² and (CH₂)_(n) SO₃— inwhich n is 1 to 12;

[0013] A² is selected from a bond, —O—, O—CO—, CO—O, CO—NR¹—, —NR¹—CO,O—CO—NR¹—, NR¹—CO—O—;

[0014] R is hydrogen or C₁₋₄ alkyl;

[0015] R¹ is hydrogen, C₁₋₄-alkyl or BX;

[0016] R² is hydrogen or C₁₋₄ alkyl;

[0017] B is a bond, or a straight branched alkanediyl, alkyleneoxaalkylene, or alkylene (oligooxalkylene) group, optionally containingone or more fluorine substituents;

[0018] X is an ammonium, phosphonium, or sulphonium phosphate orphosphonate ester zwitterionic group, are polymerised by a livingradical polymerisation process in the presence of an initiator, and acatalyst.

[0019] The zwitterionic group X, in this aspect of the invention,comprises as the cationic moiety, and ammonium, phosphonium orsulphonium group. Preferably the cation is an ammonium group. The anionof the zwitterion is a phospho moiety. It is generally a phosphatediester, or a phosphonate ester based moiety. Generally in thezwitterionic group X, the anion is closer to B than the cation. Howeverin some zwitterions, the cation-is closer to the group B than is theanion (called hereinafter phosphobetaines).

[0020] Preferably X is a group of the general formula II

[0021] in which the moieties A³ and A⁴, which are the same or different,are —O—, —S—, —NH— or a valence bond, preferably —O—, and W⁺ is a groupcomprising an ammonium, phosphonium or sulphonium cationic group and ais group linking the anionic and cationic moieties which is preferably aC₁₋₁₂-alkanediyl group,

[0022] preferably in which W⁺ is a group of formula —W¹—N⁺R³ ₃, —W¹—P⁺R⁴₃, —W¹—S⁺R⁴ ₂ or —W¹-Het⁺ in which:

[0023] W¹ is alkanediyl of 1 or more, preferably 26 carbon atomsoptionally containing one or more ethylenically unsaturated double ortriple bonds, disubstituted-aryl (arylene), alkylene arylene, arylenealkylene, or alkylene aryl alkylene, cycloalkanediyl, alkylenecycloalkyl, cycloalkyl alkylene or alkylene cycloalkyl alkylene, whichgroup W¹ optionally contains one or more fluorine substituents and/orone or more functional groups; and

[0024] either the groups R³ are the same or different and each ishydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, or aryl,such as phenyl, or two of the groups R³ together with the nitrogen atomto which they are attached form an aliphatic heterocyclic ringcontaining from 5 to 7 atoms, or the three groups R³ together with thenitrogen atom to which they are attached form a fused ring structurecontaining from 5 to 7 atoms in each ring, and optionally one or more ofthe groups R³ is substituted by a hydrophilic functional group, and

[0025] the groups R⁴ are the same or different and each is R³ or a groupOR³, where R³ is as defined above; or

[0026] Het is an aromatic nitrogen-, phosphorus- or sulphur-, preferablynitrogen-, containing ring, for example pyridine.

[0027] Monomers in which X is of the general formula in which W⁺ isW¹N.R³ ₃ may be made as described in our earlier specificationWO-A-9301221. Phosphonium and sulphonium analogues are described inWO-A-9520407 and WO-A-9416749.

[0028] Generally a group of the formula II has the preferred generalformula III

[0029] where the groups R⁵ are the same or different and each ishydrogen or C₁₋₄ alkyl, and m is from 1 to 4, in which preferably thegroups R⁵ are the same preferably methyl.

[0030] In phosphobetaine based groups, X may have the general formula IV

[0031] in which A⁵ is a valence bond, —O—, —S— or —NH—, preferably —O—;

[0032] R⁶ is a valence bond (together with A⁵) or alkanediyl,—C(O)alkylene- or —C(O)NH alkylene preferably alkanediyl, and preferablycontaining from 1 to 6 carbon atoms in the alkanediyl chain;

[0033] W² is S, PR⁷ or NR⁷;

[0034] the or each group R⁷ is hydrogen or alkyl of 1 to 4 carbon atomsor the two groups R⁷ together with the heteroatom to which they areattached form a heterocyclic ring of 5 to 7 atoms;

[0035] R⁸ is alkanediyl of 1 to 20, preferably 1 to 10, more preferably1 to 6 carbon atoms;

[0036] A⁶ is a bond, NH, S or O, pr ferably O; and

[0037] R⁹ is a hydroxyl, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₇₋₁₈ aralkyl,C₇₋₁₈-aralkoxy, C₆₋₁₈ aryl or C₆₋₁₈ aryloxy group.

[0038] Monomers comprising a group of the general formula IV may be madeby methods as-described in JP-B-03031718, in which an amino substitutedmonomer is reacted with a phospholane.

[0039] In compounds comprising a group of the general formula IV, it ispreferred that

[0040] A⁵ is a bond;

[0041] R⁶ is a C₂₋₆ alkanediyl;

[0042] W² is NR⁷:

[0043] each R⁷ is C₁₋₄ alkyl;

[0044] R⁸ is C₂₋₈ alkanediyl;

[0045] A⁶ is O; and

[0046] R⁹ is C₁₋₄ alkoxy.

[0047] In the zwitterionic monomer of the general formula I it ispreferred that the ethylenic unsaturated group Y is H₂C═CR—CO—A—. Suchacrylic moieties are preferably methacrylic, that is in which R ismethyl, or acrylic, in which R is hydrogen. Whilst the compounds may be(meth)acrylamido compounds (in which A is NR¹), in which case R¹ ispreferably hydrogen, or less preferably, methyl, most preferably thecompounds are esters, that is in which A is O.

[0048] In monomers of the general formula I, especially where Y is thepreferred (alk)acrylic group, B is most preferably an alkanediyl group.Whilst some of the hydrogen atoms of such group may be substituted byfluorine atoms, preferably B is an unsubstituted alkanediyl group, mostpreferably a straight chain group having 2 to 6 carbon atoms.

[0049] A particularly preferred zwitterionic monomer is2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt.

[0050] In the polymerisation process, the ethylenically unsaturatedmonomers may further include a comonomer. Comonomers are copolymerisablewith the zwitterionic monomer and are pref rably sel ct d from anionic,cationic and nonionic monomers. It is generally preferred that themonomer mixture include at least one nonionic monomer. Another class ofcomonomer is a cross-linking monomer having a functional group which maybe cured after polymerisation to cross-link the polymer.

[0051] Examples of suitable comonomers are compounds of the generalformula X

[0052] in which R³¹ is selected from hydrogen, halogen, C₁₋₄ alkyl andgroups COOR² in which R² is hydrogen and C₁₋₄ alkyl;

[0053] R³² is selected from hydrogen, halogen and C₁₋₄ alkyl;

[0054] R³³ is selected from hydrogen, halogen, C₁₋₄ alkyl and groupsCOOR² is provided that R³¹ and R³³ are not both COOR²; and

[0055] R³⁴ is a C₁₋₁₀ alkyl, a C₁₋₂₀ alkoxycarbonyl, a mono-or di-(C₁₋₂₀alkyl) amino carbonyl, a C₆₋₂₀ aryl (including alkaryl) a C₇₋₂₀ aralkyl,a C₆₋₂₀ aryloxycarbonyl, a C₁₋₂₀-aralkyloxycarbonyl, a C₆₋₂₀ arylaminocarbonyl, a C₇₋₂₀ aralkyl-amino, a hydroxyl or a C₂₋₁₀ acyloxy group,any of which may have one or more substituents selected from halogenatoms, alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine(including mono and di-alkyl amino and trialkylammonium in which thealkyl groups may be substituted), carboxyl, sulphonyl, phosphoryl,phosphino, (including mono- and di-alkyl phosphine andtri-alkylphosphonium), zwitterionic, hydroxyl groups, vinyloxycarbonyland other vinylic or allylic substituents, and reactive silyl orsilyloxy groups, such as trialkoxysilyl groups;

[0056] or R³⁴ and R³³ or R³⁴ and R³² may together form —CONR³⁵CO inwhich R³⁵ is a C₁₋₂₀ alkyl group.

[0057] It is preferred for at least two of the groups R³¹ R³² R³³ andR³⁴ to be halogen or, more preferably, hydrogen atoms. Preferably R³¹and R³² are both hydrogen atoms. It is particularly preferred thatcompound of general formula X be a styrene-based or acrylic basedcompound. In styrene based compounds R³⁴ represents an aryl group,especially a substituted aryl group in which the substituent is an aminoalkyl group, a carboxylate or a sulphonate group. Where the comonomer isan acrylic type compound, R³⁴ is an alkoxycarbonyl, an alkyl aminocarbonyl, or an aryloxy carbonyl group. Most preferably in suchcompounds R³⁴ is a C₁₋₂₀-alkoxy carbonyl group, optionally having ahydroxy substituent. Acrylic compounds are generally methacrylic inwhich case R³³ is methyl.

[0058] Where a comonomer is included in the polymerisation process ofthe invention, the molar ratio of zwitterionic monomer to comonomer ispreferably in the range 1:50 to 50:1, more preferably in the range 1:10to 10:1, more preferably in the range 1:5 to 1:1.

[0059] The living radical polymerisation process of the invention may bea group transfer radical polymerisation, for instance in which an N→O,or other carbon-, sulphur-, and oxygen-centered radical group istransferred from an initiator compound to a monomer. Preferably,however, the process is an atom transfer radical polymerisation process.

[0060] In the atom or group transfer radical polymerisation process, theinitiator has a radically transferable atom or group, and the catalystcomprises a transition metal compound and a ligand, in which thetransition metal compound is capable of participating in a redox cyclewith the initiator and dormant polymer chain, and the ligand is eitherany N-, O-, P- or S-containing compound which can-coordinate with thetransition metal atom in a σ-bond, or any carbon-containing compoundwhich can coordinate with the transition metal in a π-bond, such thatdirect bonds between the transition metal and growing polymer radicalsand not formed.

[0061] Preferably the radical initiator is of the general formula V

R¹¹R¹²R¹³C—X²  V

[0062] where:

[0063] X² is selected from the group consisting of Cl, Br, I, OR¹⁰,SR¹⁴, SeR¹⁴, OP(═O)R¹⁴, OP(═O)(OR¹⁴)₂; O—N(R¹⁴)₂ and S—C(═S)N(R¹⁴)₂₃where R¹⁰ is alkyl of from 1 to 20 carbon atoms in which each of thehydrogen atoms may be independently replaced by halide, R¹⁴ is aryl or astraight or branched C₁-C₂₀ alkyl group, and wher an N(R¹⁴)₂ group ispresent, the two R¹⁴ groups may be joined to form a 5- or 6-memberedheterocyclic ring; and

[0064] R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of H, halogen, C₁-C₂₆ alkyl, C₃-C₈ cycloalkyl, C(═O)R¹⁵,C(═O)NR¹⁶R¹⁷, COCl, OH, CN, C₂-C₂₀ alkenyl, C₂-C₂₀ alkenyl oxiranyl,glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, C₁₋-C₆ alkyl in whichfrom 1 to all of the hydrogen atoms are replaced with halogen, C₁-C₆alkyl substituted with from 1 to 3 substituents selected from the groupconsisting of C₁-C₄ alkoxy, aryl, heterocyclyl, C(═O)R¹⁵, C(═O)NR¹⁶R¹⁷,—CR¹²R¹³X² oxiranyl and glycidyl;

[0065] where R¹⁵ is alkyl of from 1 to 20 carbon atoms, alkoxy of from 1to 20 carbon atoms, oligo(alkoxy) in which each alkoxy group has 1 to 3carbon atoms, aryloxy or heterocyclyloxy any of which groups may havesubstituents selected from optionally substituted alkoxy, oligoalkoxy,amino (including mono- and di-alkyl amino and trialkyl ammonium, whichalkyl groups, in turn may have substiuents selected from acyl,alkoxycarbonyl, alkenoxycarbonyl, aryl and hydroxy) and hydroxyl groups;and

[0066] R¹⁶ and R¹⁷ are independently H or alkyl of from 1 to 20 carbonatoms which alkyl groups, in turn may have substiuents selected fromacyl, alkoxycarbonyl, alkenoxycarbonyl, aryl and hydroxy, or R¹⁶ and R¹⁷may be joined together to form an alkanediyl group of from 2 to 5 carbonatoms, thus forming a 3- to 6-membered ring;

[0067] such that not more than two of R¹¹, R¹² and R¹³ are H.

[0068] In the initiator of the general formula V it is preferred that nomore than one of R¹¹, R¹² and R¹³, and preferably none, is hydrogen.Suitably at least one, and preferably both of R¹¹ and R¹² is methyl. R¹³is suitably a group CO—R¹⁵ in which R¹⁵ is preferably alkoxy of from 1to 20 carbon atoms, oligo(alkoxy) in which each alkoxy group has 1 to 3carbon atoms, aryloxy or heterocyclyloxy any of which groups may havesubstituents selected from optionally substituted alkoxy, oligoalkoxy,amino (including mono- and di-alkyl amino and trialkyl ammonium, whichalkyl groups, in turn may have substiuents selected from acyl,alkoxycarbonyl, alkenoxycarbonyl, aryl and hydroxy) and hydroxyl groups.

[0069] Since any of R¹¹, R¹² and R¹³ may comprise a substituentC¹²R¹³X², the initiator may be di-, oligo- or poly-functional.

[0070] Selection of a suitable initiator is based on variousconsiderations. Where the polymerisation is carried out in the liquidphase, in which the monomers are dissolved, it is preferable for theinitiator to be soluble in that liquid phase. The initiator is thusselected for its solubility characteristics according to the solventsystem which in turn is selected according to the monomers beingpolymerised. Also the choice of monomer will affect the polymerarchitecture. Star, comb, block or linear polymers may be selected bychoice of a suitable initiator. A star initiator could be synthesisedfrom a halogenated sugar. A comb initiator could be based on a polymerwith pendant halogenated groups. Water-soluble initiators include, forinstance is the reaction product of monomethoxy-capped oligo(ethyleneoxide) with 2-bromoisobutyryl bromide (OEGBr), 4-bromo-α-toluic acid orethyl 2-bromopropanoic acid or 2-(N,N-dimethylamino)ethyl-2′-bromoisobutyrate.

[0071] From the general reaction scheme shown above, it is clear thatthe portion of the initiator —C—R¹¹R¹²R¹³ becomes joined to the firstmonomer of the growing polymer chain. The group X² becomes joined to theterminal unit of the polymer chain. Selection of a suitable initiator isdetermined in part by whether a terminal group having particularcharacteristics is required for subsequent functionality. Subsequentreactions of the product polymer are described below.

[0072] In the atom or group radical transfer polymerisation process thetransition metal compound which comprises a component of the catalyst isM_(t) ^(n+)X′_(n), where:

[0073] M_(t) ^(n+) may be selected from the group consisting of Cu¹⁺,Cu²⁺, Fe²⁺, Fe³⁺, Ru²⁺, Ru³⁺, Cr²⁺, Cr³⁺, Mo²⁺, Mo³⁺, W²⁺, W³⁺, Mn²⁺,Mn³⁺, Mn⁴⁺, Rh³⁺, Rh⁴⁺, Re²⁺, Re³⁺, Co⁺, Co²⁺, Co³⁺, V²⁺, V³⁺, Zn⁺,Zn²⁺, Ni²⁺, Ni³⁺, Au⁺, Au²⁺, Ag⁺ and Ag²⁺;

[0074] X′ is selected from the group consisting of halogen,C₁-C₆-alkoxy, (SO₄)_(1/2), (PO₄)_(1/3), (R¹⁸PO₄)_(1/2),(R¹⁸ ₂PO₄),triflate, hexafluorophosphate, methanesulphonate, arylsulphonate, CN andR¹⁹CO₂, where R¹⁸ is aryl or a straight or branched C₁₋₂₀ alkyl and R¹⁹is H or a straight or branched C₁-C₆ alkyl group which may besubstituted from 1 to 5 times with a halogen; and

[0075] n is the formal charge on the metal (0≦n≦7).

[0076] Preferably X′ is halide, most preferably chloride or bromide.Particularly suitable transition metal compounds are based on copper orruthenium, for instance CuCl or RuCl₂.

[0077] In the catalyst, the ligand is preferably selected from the groupconsisting of:

[0078] a) compounds of the formulas:

R²⁰-Z-R²¹ and

R²⁰-Z-(R²²-Z)_(m)—R²¹

[0079] where:

[0080] R²⁰ and R²¹ are independently selected from the group consistingof H, C₁-C₂₀ alkyl, aryl, heterocyclyl and C₁-C₆ alkoxy, C₁-C₄dialkylamino, C(═O)R²², C(═O)R²³R²⁴ and A⁷C(═O)R²⁵, where A⁷ may be NR²⁶or O; R²² is alkyl of from 1 to 20 carbon atoms, aryloxy orheterocyclyloxy; R²³ and R²⁴ are independently H or alkyl of from 1 to20 carbon atoms or R²³ and R²⁴ may be joined together to form analkanediyl group of from 2 to 5 carbon atoms, thus forming a 3- to6-membered ring; R²⁵ is H, straight or branched C₁-C₂₀ alkyl or aryl andR²⁶ is hydrogen, straight or branched; C₁₋₂₀-alkyl or aryl; or R²⁰ andR²¹ may be joined to form, together with Z, a saturated or unsaturatedring;

[0081] Z is O, S, NR²⁷ or PR²⁷, where R²⁷ is selected from the samegroup as R²⁰ and R²¹, and where Z is PR²⁷, R²⁷ can also C₁-C₂₀ alkoxy orZ may be a bond, CH₂ or a fused ring, where one or both of R²⁰ and R²¹is heterocyclyl,

[0082] each R²² is independently a divalent group selected from thegroup consisting of C₁-C₈ cycloalkanediyl, C₁-C₈ cycloalkenediyl,arenediyl and heterocyclylene where the covalent bonds to each Z are atvicinal positions or R²² may be joined-to one or both of R²⁰ and R²¹ toformulate a heterocyclic ring system; and

[0083] m is from 1 to 6;

[0084] b) CO;

[0085] c) porphyrins and porphycenes, which may be substituted with from1 to 6 halogen atoms, C₁₋₆ alkyl groups, C₁₋₆-alkoxy groups, C₁₋₆alkoxycarbonyl, aryl groups, heterocyclyl groups, and C₁, alkyl groupsfurther substituted with from 1 to 3 halogens;

[0086] d) compounds of the formula R²³R²⁴C(C(═O)R²⁵)₂, where R^(25 is)C₁₋₂₀ alkyl, C₁₋₂₀ alkoxy, aryloxy or heterocyclyloxy; and each of R²³and R²⁴ is independently selected from the group consisting of H,halogen, C₁₋₂₀ alkyl, aryl and heterocyclyl, and R²³ and R²⁴ may bejoined to form a C₁₋₈ cycloalkyl ring or a hydrogenated aromatic orheterocyclic ring, of which the ring atoms may be further substitutedwith 1 to 5 C₁₋₆ alkyl groups, C₁₋₆ alkoxy groups, halogen atoms, arylgroups, or combinations thereof; and

[0087] e) arenes and cyclopentadienyl ligands, where saidcyclopentadienyl ligand may be substituted with from one to five methylgroups, or may be linked through and ethylene or propylene chain to asecond cyclopentadienyl ligand.

[0088] Selection of a suitable ligand is, for instance, based upon thesolubility characteristics and/or the separability of the catalyst fromthe product polymer mixture. Generally it is catalyst to be soluble in aliquid reaction mixture, although under some circumstances it may bepossible to immobilise the catalyst, for instance an a porous substrate.For the preferred process, which is carried out in the liquid phase, theligand is soluble in a liquid phase. The ligand is generally a nitrogencontaining ligand. The preferred-ligand maybe a compound including apyridyl group and an imino moiety, such as bipyridine, or

[0089] where R is a suitable alkyl group, the substituent being variableand adaptable to confer desired solubility characteristics or may betriphenylphosphine or 1,1,4,7,10,10-hexamethyl-triethylene tetramine.

[0090] Such ligands are usefully used in combination with copperchloride and ruthenium chloride transition metal compounds as part ofthe catalyst.

[0091] The living radical polymerisation process of the invention ispreferably carried out to achieve a degree of polymerisation inthe-range 5 to 500. Preferably the degree of polymerisation is in therange 10 to 100, more preferably in the range 10 to 50. In the preferredgroup or atom transfer radical polymerisation technique, the degree ofpolymerisation is directly related to the initial ratios of initiator tomonomer. Preferably the ratio is in the range 1:(5 to 500), morepreferably in the range of 1:(10 to 100), most preferably in the range1:(10 to 50).

[0092] The ratio of metal compound and ligand in the catalyst should beapproximately stoichiometric, based on the ratios of the components whenthe metal ion is-fully complexed. The ratio should preferably be in therange 1:(0.5 to 2) more preferably in the range 1:(0.8:1.25). Preferablythe range is about 1:1.

[0093] In the process, the catalyst may be used in amounts such that amolar equivalent quantity as compared to the level of initiator ispresent. However, since catalyst is not consumed in the reaction, it isgenerally not essential to include levels of catalyst as high as ofinitiator. The ratio of catalyst (based on transition metal compound) toinitiator is preferably in the range 1:(1 to 50), more preferably in therange 1:(1 to 10).

[0094] Whilst the polymerisation reaction-may be carried out in thegaseous phase, it is more preferably carried out in the liquid phase.The reaction may be heterogeneous, that is comprising a solid and aliquid phase, but is more preferably homogeneous. Preferably thepolymerisation is carried out in a single liquid phase. Where themonomer is liquid, it is sometimes unnecessary to include anon-polymerisable solvent. More often, however, the polymerisation takesplace in the presence of a non-polymerisable solvent. The solvent shouldbe selected having regard to the nature of the zwitterionic monomer andany comonomer, for instance for its suitability for providing a commonsolution containing both monomers. The solvent may comprise a singlecompound or a mixture of compounds.

[0095] It has been found that, especially where the zwitterionic monomeris MPC, that it is desirable to include water in the polymerisationmixture. Preferably water should be present in an amount in the range 10to 100% by weight based on the weight of ethylenically unsaturatedmonomer. Preferably the total non-polymerisable solvent comprised 1 to500% by weight based on the weight of ethylenically unsaturated monomer.It has been found that the zwitterionic monomer and water should be incontact with each other for as short a period as possible prior tocontact with the initiator and catalyst. It may be desirable thereforefor all the components of the polymerisation other than the zwitterionicmonomer to be premixed and for the zwitterionic-monomer to be added tothe premix as the last additive.

[0096] It is often desired to copolymerise MPC or other zwitterionicmonomer with a comonomer-which is insoluble in water. Insuch-circumstances, a solvent or co-solvent (in conjunction with water)is included to confer solubility on both MPC and the more hydrophobicmonomer. Suitable organic solvents are ethers, esters and, mostpreferably, alcohols. Especially where a mixture of organic solvent andwater is to used, suitable alcohols are C₁₋₄-alkanols. Methanol is foundto be particularly suitable in the polymerisation process of theinvention.

[0097] The process may be carried out at raised temperature, forinstance up to 60 to 80° C. However it has been found that the processproceeds sufficiently fast at ambient temperature.

[0098] The polymerisation process of the invention has been found toprovide polymers of zwitterionic monomers having a pblydispersity (ofmolecular weight) of less than 1.5, as judged by gel permeationchromatography. Polydispersities in the range 1.2 to 1.4 have beenachieved. Conversion rates achieved in the process are over 90% oftenover 95% or higher. It is preferred that the process be continu d untila conversion level of at least 50%, or usually, at l ast 70% is reached.

[0099] It is believed that this process is the first time that lowpolydispersity polymers have been formed of monomers of the generalformula I and such polymers form a further aspect of the invention.

[0100] Such polymers are preferably made by the living radicalpolymerisation process of the first aspect of the invention. Othercontrolled polymerisation techniques may be used for instance NO grouptransfer: systems such as are described in WO-A-0018807, catalystsystems described in WO-A-9958588, systems involving irradiation withvisible light, or other EM radiation such as described in WO-A-99/10387,radical addition fragmentation chain transfer polymerisation (RAFT) asdescribed in Rizzardo, E. et at ACS Symposium Series 2000, 768, 278-296,using compounds (initiators) of the general type Z-C═SSR ormacromolecular design through interchange of xanthes (MADIX) as descriedby Bontevin, B., J. Polym. Sci. PtA, Polym. Chem., 2000, 38(18),3235-3243.

[0101] The polymer product of the polymerisation process of theinvention may be a useful product as such. It may be desirable todeactivate or functionalise the terminal groups, that is the CR¹¹R¹²R¹³and/or X² groups. The presence of such groups in the final polymer mayprovide useful functionality for subsequent chemical reactions. Forinstance tertiary amine substituents in such groups may be quatemised,ethylenic groups may be polymerised, and crosslinkable groups may becured.

[0102] The product polymer may be a useful intermediate for formingblock copolymers. A product polymer having a single terminal group X²may be used as an initiator in a second group or atom transfer radicalpolymerisation step carried out in the presence of a catalyst, andadditional ethylenically unsaturated monomer. The product will be ablock copolymer of the A-B type. The second block may be of the same or,more usefully, a different composition to that of the initial block A.The monomers from which block A and block B are formed may comprise thesame component but in different ratios. More often they comprisedifferent monomers, although they may include common comonomers. Asecond block, for instance added to a block A formed from zwitterionicmonomer, may comprise ionic monomer or nonionic monomer. Nonionicmonomer may be selected so as to confer hydrophobicity or control thehydrophilicity of the block copolymer. Suitable monomers used in asecond living polymerisation step may include monomers of the generalformula V, defined above. Comonomers may be selected to conferbiodegradability upon the block copolymers.

[0103] A block copolymer of the A-B-A type may be produced where theinitiator of a first step living polymerisation was difunctional,generating a single block B having two terminal groups X² (and a unitderived from the initiator partway along the backbone). In the secondliving polymerisation step, blocks of A will be added at each end of theinitial polymer product. Alternatively, block copolymers having a startype architecture may be generated starting from a multifunctionalinitiator in the first step producing a star intermediate having, ateach terminal, a X² group, from which the second step polymerisationpropagates.

[0104] According to a second aspect of the invention there is provided ablock copolymer of the A-B or A-B-A type in which A and B are the sameor, preferably, different, in which at least one of the A and B isformed from ethylenically unsaturated monomer including a zwitterionicmonomer of the general formula VI

Y B X¹  VI

[0105] in which Y is an ethylenically unsaturated group selected fromH₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A², R²O—CO—CR═CR—CO—O,RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

[0106] A is —O— or NR¹;

[0107] A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n) SO₃— inwhich n is 1 to 12;

[0108] A² is selected from a bond —O—, O—CO—, CO—O, CO—NR¹—, —NR¹—CO,O—CO—NR¹—, NR¹—CO—O—;

[0109] R is hydrogen or C₁₋₄ alkyl;

[0110] R¹ is hydrogen, C₁₋₄ alkyl or BX;

[0111] R² is hydrogen or C₁₋₄ alkyl;

[0112] B is a bond, or a straight branched alkanediyl, alkyleneoxaalkylene, or alkylene (oligooxalkylene) group, optionally containingone or more fluorine substituents; and

[0113] X¹ is a zwitterionic group.

[0114] In this aspect of the invention, the zwitterionic group X¹ may bea group X as defined in the first aspect of the invention. Alternativelyit may be a zwiitterion in which the anion comprises a sulphate,sulphonate or carboxylate group.

[0115] One class of zwitterions are sulphobetaines groups, for instanceof the general formula XI.

[0116] where the groups R³⁶ are the same or different and each ishydrogen or C₁₋₄ alkyl and s is from 2 to 4.

[0117] Preferably the groups R³⁶ are the same. It is also preferablethat at least one of the groups R³⁶ is methyl, and more preferable thatthe groups R³⁶ are both methyl.

[0118] Preferably s is 2 or 3, more preferably 3.

[0119] Alternatively the zwitterionic group may be an amino acid moietyin which the alpha carbon atom (to which an amine group and thecarboxylic acid group are attached) is joined through a linker group tothe backbone of the biocompatible polymer. Such groups may berepresented by the general formula XII

[0120] in which A⁷ is a valence bond, —O—, —S— or —NH—, preferably —O—,

[0121] R³⁷ is a valence bond (optionally together with A⁷) oralkanediyl, —C(O)alkylene- or —C(O)NHalkylene, preferably alkanediyl andpreferably containing from 1 to 6 carbon atoms; and

[0122] the groups R³⁸ are the same or different and each is hydrogen oralkyl of 1 to 4 carbon atoms, preferably-methyl, or two or three of thegroups R³⁸, together with the nitrogen to which they are attached, forma heterocyclic ring of from 5 to 7 atoms, or the three group R³⁸together with the nitrogen atom to which they are attached form a fusedring heterocyclic structure containing from 5 to 7 atoms in each ring.

[0123] Alternatively the zwitterion may be a carboxy betaine—N.(R³⁹)₂(CH₂)_(r)COO. in which the R³⁹ groups are the same or differentand each is hydrogen or R₁₋₄ alkyl and r is 2 to 6, preferably 2 or 3.

[0124] In this aspect of the invention it may either be the first formedblock which comprises zwitterionic monomer, or the second formed block.It is preferred that either or both blocks are formed by livingpolymerisation techniques, that is that the population of polymersshould have a low spread of block sizes, and of overall polydispersityof weight. Preferably both blocks are formed by atom or group transferradical polymerisation. At least one of the steps of a two step processis that a polymerisation process according to the first aspect of theinvention, namely the step in which the ethylenically unsaturatedmonomers include zwitterionic monomer. In a two step polymerisation bothbeing carried out by atoms or group radical transfer, the group or atomtransferred, as the case may be, will be the same in the two step. Thetransferable group which is the terminal group of the polymer product ofthe first step is transferred to a transition metal compound in theinitiation of the second step. Generally it is convenient to use thesame catalyst. In some circumstances, however, it may be necessary touse a different catalyst, for instance a different transition metalcompound or ligand, or both, if the environment in the second step ofthe polymerisation is very different from that of the first step. Forinstance where the monomers in the second step require selection of adifferent solvent-to solubilise the components, a different catalyst maybe selected. Accordingly it may be necessary to isolate the polymerintermediate of step one from the catalyst, prior to providing thereaction mixture for step two. Suitable separation methods involve, forinstance, chromatographic techniques such as gel permeation orprecipitation etc. Preferably, however, the product of step one, in itsentirety, forms part of the reaction mixture for step two.

[0125] The intermediate polymer produced by the process of the firstaspect of the invention may be a useful commercial product in its ownright, for instance having utility as an initiator for group or atomtransfer radical polymerisations. Alternatively the terminating groupsderived from the is initiator may be subjected to derivatisationreactions to introduce useful functionalities such as ionic groupsand/or ethylenically unsaturated groups.

[0126] According to a further aspect of the invention there is provideda novel polymer of the formula VIII

[0127] in which X² is selected from the group consisting of Cl, Br, I,OR¹⁰, SR¹⁴, SeR¹⁴, OP(═O)R¹⁴, OP(═O)(OR¹⁴)₂, O—N(R¹⁴)₂ andS—C(═S)N(R¹⁴)₂, where R¹⁰ is alkyl of from 1 to 20 carbon atoms in whicheach of the hydrogen atoms may be independently replaced by halide, R¹⁴is aryl or a straight or branched C₁-C₂₀ alkyl group, and where anN(R¹⁴)₂ group is present, the two R¹⁴ groups may-be joined to form a 5or 6-membered heterocyclic ring; and

[0128] R¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of H, halogen, C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl, C(═O)R¹⁵,C(═O)NR¹⁶R¹⁷, COCl, OH, CN, C₂-C₂₀ alkenyl, C₂-C₂₀ alkenyl oxiranyl,glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, C₁₋-C₆ alkyl in whichfrom 1 to all of the hydrogen atoms are replaced with halogen, and C₁-C₆alkyl substituted with from 1 to 3 substituents selected from the groupconsisting of C₁-C₄ alkoxy, aryl, heterocyclyl, C(═O)R¹⁵, C(═R)NR¹⁶Rc,—CR¹²R¹³X², oxiranyl and glycidyl;

[0129] where R¹⁵ is alkyl of from 1 to 20 carbon atoms, alkoxy of from 1to 20 carbon atoms, oligo(alkoxy) in which each alkoxy group has 1 to 5carbon atoms, aryloxy or heterocyclyloxy any of which groups may havesubstituents selected from optionally substituted alkoxy, oligoalkoxy,amino (including mono- and di-alkyl amino and trialkyl ammonium, whichalkyl groups, in turn may have substiuents selected from acyl,alkoxycarbonyl, alkenoxycarbonyl, aryl and hydroxy) and hydroxyl groups;and R¹⁶ and R¹⁷ are independently-H or alkyl of from 1 to 20 carbonatoms which alkyl groups, in turn may have substiuents selected fromacyl, alkoxycarbonyl, is alkenoxycarbonyl, aryl and hydroxy, or R¹⁶ andR¹⁷ may be joined together to form an alkylene group of from 2 to 5carbon atoms, thus forming a 3- to 6-membered ring;

[0130] such that not more than two of R¹¹, R¹² and-R¹³ are H;

[0131] M¹ is the residue of a zwitterionic monomer zwitterionic monomerof the general formula I

Y B X  I

[0132] in which Y is an ethylenically unsaturated group selected fromH₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A², R²O—CO—CR═CR—CO—O,RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

[0133] A is —O— or NR¹;

[0134] A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n) SO₃— inwhich n is 1 to 12;

[0135] A² is selected from a bond —O—, O—CO—, CO—O, CO—NR¹—, —NR¹—CO,O—CO—NR¹—, NR¹—CO—O—;

[0136] R is hydrogen or C₁₋₄ alkyl;

[0137] R¹ is hydrogen, C₁₋₁alkyl or BX;

[0138] R² is hydrogen or C₁₋₄ alkyl;

[0139] B is a bond, or a straight branched alkanediyl, alkyleneoxaalkylene, or alkylene (oligooxalkylene) group, optionally containingone or more fluorine substituents;

[0140] X is an ammonium, phosphonium, or sulphonium phosphate orphosphonate ester zwitterionic group;

[0141] X is 2 to 500;

[0142] M² is the residue of an ethylenically unsaturated comonomerpolymerisable with the zwitterionic monomer; and

[0143] y is 0 to 500.

[0144] In a preferred polymer of this aspect in the general formula VIIIM¹ preferably has the formula IX

[0145] in which R²⁷ is selected from hydrogen C₁₋₄ alkyl and groups COOR² in which R² is hydrogen or C₁₋₄ alkyl;

[0146] R²⁸ is selected from hydrogen and C₁₋₄ alkyl;

[0147] R²⁹ is selected from hydrogen, C₁₋₄alkyl and groups CO OR²,provided that R²⁷ and R²⁹ are not both CO OR²;

[0148] R³⁰ is selected from a bond, a group CH₂A² in which A² isselected from a bond, —O—, —O—CO—, —CO—O—, —CO—NR¹—, —NR¹—CO—,—O—CO—NR¹— and —NR¹—CO—O, a group —COA— in which A is —O— or NR¹, inwhich R¹ is hydrogen or C₁₋₄ alkyl or BX, and a group —C₆H₄-A¹— in whichA¹ is (CH₂)_(n)A², a bond or (CH₂)_(n) SO₃,

[0149] or R³⁰ and R²⁸ or R³⁰ and R²¹ may be joined to form a group

[0150] where the N atom is joined to B;

[0151] and B and X are as defined above.

[0152] In the polymer of the general formula VIII, M² is preferably theresidue of a monomer of the general formula X as described above. Thegroup M², derived from such a monomer will have the general formula

[0153] —C(R³¹)(R³²—C(R³³)R³⁴), in which R³¹ through R³⁴ have the samemeanings as in the general formula X.

[0154] In the polymer of the general formula X, R¹¹, R¹² and R¹³ as wellX² have the preferred meanings ascribed to the respective groups in theinitiator described in relation to the first aspect of the inventionabove. Thus X² is preferably halogen, more preferably Cl or Br.Preferably no more than one of R¹¹, R¹² and R¹³ is hydrogen, morepreferably none is hydrogen.

[0155] In the general formula VIII the residues of M² are randomlydispersed among the residues of M¹.

[0156] In the invention, the controlled molecular weight, compositionand architectures of these various product polymers bring aboutdesirable levels of control in the properties of the polymers. Forinstance, the provision of blocks of substantially homopolymer of unitsderived from zwitterionic monomer are believed to confer desirablewettability and/or lubricity. In AB block copolymers or polymers formedusing oligomeric initiators such as based on oligo(alkylene oxides), theprovision of long blocks of hydrophobic units are likely to formdiscrete domains. The domains of highly hydrophilic and highlyhydrophobic composition may be useful for controlling polymerproperties, such as interactions with other components in a desiredsystem, especially for the absorption and controlled delivery of drugsor other active compounds, and for providing spontaneouslyself-assembling structures such as coatings, or vesicles or micelleshaving domains of hydrophilic and domains of hydrophobic nature. Thesemay be useful for controlling absorption and release or solubility ofbiologically active compounds such as pharmaceuticals. Vesicles mayform, with dehydrated or hydrophobic layers or cores and zwitterionicexteriors in aqueous environments. The external zwitterionic layershould confer good biocompatibility, for instance resistance tophagocytosis when administered in vivo. This may be a useful drugdelivery device, therefore.

[0157] The invention is illustrated further in the accompanyingexamples, and figures.

[0158]FIGS. 1 and 2 are plots of the reaction kinetics of Example 1;

[0159]FIG. 3 is the ¹H NMR spectrum of the polymer produced in Example 1

[0160]FIGS. 4 and 5 are plots of the reaction kinetics of Example 3;

[0161]FIGS. 6 and 7 are ¹H NMR spectra of the block copolymer producedin Example 4 and pH 9 and 3, respectively;

[0162]FIG. 8 is a ¹H NMR spectrum of the block copolymer produced inExample 24 at two pH's as described in Example 30;

[0163]FIG. 9 shows the ¹H NMR spectrum and chemical formulae for theinitiator, monomer and polymer of Example 31;

[0164]FIG. 10 shows the ¹H NMR during the polymerisation process ofExample 31;

[0165]FIG. 11 indicates drug loading levels in Example 58; and

[0166]FIG. 12 indicates drug release levels in Example 58.

EXAMPLE 1 Homopolymerisation of MPC (1) via ATRP in Water

[0167] With reference to FIG. 1, a typical protocol for the controlledpolymerisation of 1 by aqueous ATRP is as follows. A water-soluble ATRPinitiator (OEGBr, 413 mg, 0.67 mmol, 1 equiv.) was synthesised asreported previously E. J. Ashford, V. Naldi, R. O'Dell, N. C. Billinghamand S. P. Armes, Chem. Commun., 1285, 1999 and dissolved indoubly-distilled, de-ionised water (10 ml). After purging with nitrogenfor 30 min. Cu(I)Br catalyst (96 mg, 0.67 mmol, 1 equiv.) and bipyridine(bpy) ligand (208 mg, 0.13 mmol, 2 equiv.) were added to the stirredsolution under a flow of nitrogen. Monomer 1 (2 g, 6.7 mmol, 10 equiv.)was then added as a solid to the reaction mixture under nitrogen. Thereaction mixture immediately became dark green and progressively moreviscous. Exotherms of 2-4° C. were typically observed, indicating thatpolymerisation was occurring. After the reaction was complete theresulting homopolymer 1 was precipitated from THF, then redissolved inwater and passed through a silica column to remove residual ATRPcatalyst.

[0168] Further polymerisations were conducted at differentconcentrations and ratios of monomer and initiator. In all cases theATRP of 1 in water was rapid: exotherms of around 3° C. were observedand near-quantitative yields (>96%) were obtained within 10 minutes at20° C. and 17 wt. % monomer concentration. At higher monomerconcentration (40 wt. %) yields of more than 96% were obtained within 3minutes. However, polydispersities were a little higher at 1.23-1.45,indicating some loss of control under these conditions.

[0169] The semi-logarithmic kinetic plot for the homopolymerisation of 1Conditions: [monomer]=17 wt. %, [initiator]=24 mM; pH 7; the molar ratioof monomer: initiator copper(1): bpy was 28:1:1:2, 20° C.) is linear forthe first 50% of the polymerisation (see FIG. 1). At higher conversionsnon-linear behaviour is observed, indicating that the polymer radicalconcentration is no longer constant. On the other hand, the evolution ofmolecular weight with conversion is highly linear up to 95% conversion(see FIG. 2).

[0170] Molecular weight distributions were assessed using GPC (1.0 MNaCl solution with 50 mM Trisma buffer, Superdex 200 column, PEOstandards, RI detector). The kinetics of polymerisation were monitoredby ¹H NMR spectroscopy by comparing the peak integrals due to themonomer vinyl signals (at δ 5.5 and 5.9) to those of the methacrylatebackbone (at δ 0.5 to 1.1) (see FIG. 3).

[0171] GPC analysis indicates narrow, unimodal molecular weightdistributions, with polydispersities (Mw/Mn) of around 1.1 to 1.45 (seeTable 1). The initiator was used as an ‘end-group’ to determine thedegrees of polymerisation of the homopolymers by ¹H NMR spectroscopy(see Table 1). In these calculations it is assumed that the initiatorefficiency is 100%, chain transfer is negligible and that every polymerchain contains an oligo(ethylene glycol) fragment. The latter assumptionwas confirmed by the following experiment. An aqueous solution of poly1(degree of polymerisation=20) was precipitated into THF, which is a goodsolvent for the oligo(ethylene glycol)-based initiator. No change in thedegree of polymerisation of the precipitated homopolymer was detected byNMR, which confirmed that all of the initiator groups were covalentlyattached to the polymer chains, as expected. For this example onlyrelatively low degrees of polymerisation were targeted, partly becauseof the known exclusion limits of our GPC column.

EXAMPLE 2 Homopolymerisation of MPC via ATRP in Methanol

[0172] The feasibility of polymerising 1 in methanol at 20° C. was alsoinvestigated. Well-controlled ATRP occurred much more slowly under theseconditions, with conversions of only 70% after 4 h. Aqueous GPC analysisindicated a final polydispersity of 1.12 at a monomer-concentration of17 wt. %. However, ATRP in aqueous media is preferred since very highyields are achieved much more efficiently (Table 1). TABLE 1 Summary ofsynthesis conditions, molecular weight data and conversions for thehomopolymerisation of the phosphorylcholine-based monomer (1) via ATRPat 20° C. in either water or methanol. [Monomer] [Initiator] Solvent(wt. %) (mM) TheoreticalDp Experimental Dp^(a) Experimental M_(n) ^(b)M_(w)/M_(n) ^(b) Conversion (%) H₂O 17 0 c c c c     53^(c) H₂O 17 67 1011 4,710 1.18 >96 H₂O 17 40 17 18 6,900 1.28 >96 H₂O 40 222 10 10 4,2301.23 >96 H₂O 40 111 20 20 7,550 1.39 >96 H₂O 40 73 30 29 10,720 1.45 >96MeOH 17 67 10 11 3,800 1.12 >96 MeOH 40 73 30 29 8,640 1.41 >96

EXAMPLE 3 Homopolymerization of MPC in H₂O via ATRP Using Methanol as aCo-Solvent

[0173] A two-neck round-bottom 100 ml flask was charged with OEG-Br,CuCl and bipy. Water (8.0 ml) was added and-the mixture was stirreduntil a homogeneous solution was obtained. Monomer 1 (2.0 g) wasdissolved in degassed methanol (2.0 ml), added to the reaction solutionand the flask was sealed with a rubber septum. The reaction mixture wasmaintained under dry nitrogen for the duration of the polymerisation.The molar ratio of [1]:[CuCl]:[bipy]:[initiator] used in this case was20:1:2:1, i.e. the target Dp was 20.

[0174] A plot of ln([M]₀/[M]) against time homopolymerisation of HEMA-PCat 20° C. [HEMA-PC]₀=0.67 M; [OEG₃₅₀-Br]₀=0.033 M; [CuCl]₀=0.033 M;[bipy]₀=0.066M; H₂O=8.0 ml, MeOH=2.0 ml was linear and passed throughthe origin, demonstrating that the radical concentration remainedconstant on the time-scale of the polymerisation, see FIG. 4. Theexperimental M, valu s obtained from ¹H NMR agreed well with thetheoretical line, see FIG. 5 (same conditions). Polydispersitiesremained low throughout the polymerisation (Mw/Mn≦51.3) which isindicative of a living polymerisation. In summary, methanol can be usedas a co-solvent for 1 which enables this monomer to be convenientlyhandled as a solution, rather than as a solid. If the methanol contentis relatively low (in this case 20 vol %) there appears to be nodetrimental effect on the rate of polymerisation. TABLE 2 Kinetic datafor the homopolymerisation of HEMA-PC via ATRP in 20:80 methanol/watermixture at 20° C. The conditions were: [HEMA-PC] = 0.67 M, [OEG-Br] =0.033 M, [CuCl] = 0.033 M, [bipy] = 0.066 M, H₂O = 8.0 ml, MeOH = 2.0ml. Time Conv Mn Mn No. (min.) (%) (theory) (NMR) Mw/Mn 1 0.5 4 259 2911.14 2 1 8 466 437 1.17 3 2 13 768 728 1.19 4 5 35 2060 1770 1.21 5 1061 3590 3160 1.22 6 20 86 5070 4410 1.26 7 35 99 5810 5180 1.31

EXAMPLE 4 AB-Diblock MPC-NaVBA Copolymer Formation via ATRP

[0175] Diblock copolymers based on 1 can also be synthesised via aqueousATRP. For example, sodium 4-vinylbenzoate (NaVBA) (0.5 g, 3.4 mmol) washomopolymerised ([NaVBA]=13 wt. %, [I]=20 mM, D=46) to high yield (>90%)in water (3.5 ml) at pH 11 and 20° C. using OEGBr as initiator, asdescribed previously X. S. Wang, R. A. Jackson and S. P. Armes,Macromolecules, 2000, 33, 255.¹³ At this point monomer 1 (1.0 g, 3.4mmol) was added as a solid to this reaction solution ([1]=22 wt. %,[I]=20 mM, theoretical D_(p)=46) to form a diblock copolymer.

[0176]¹H NMR studies indicated that the block copolymer comprisedapproximately 55 mol % NaVBA, theoretical D_(p)(NaVBA)=46, D_(p)(1)=37,see FIG. 6. This block copolymer dissolved molecularly in water at pH 7but formed micellar aggregates reversibly on addition of acid (pH 3),see FIG. 7. Dynamic light scattering studies indicated a bimodal sizedistribution, with the larger population having an intensity-averagemicelle diameter of 190 nm. ¹H NMR studies of these micelles in DCI/D₂Omixtures confirmed that the 4-vinylbenzoic acid residues formed thedehydrated micelle cores and the phosphorylcholine-based residues formedthe micelle coronas, as expected. Such micelles might be expected to actas ‘stealth’ nanoparticles for in vivo biomedical applications, sincethe phosphorylcholine outer layer should minimise protein adsorption andhence prevent phagocytosis.

EXAMPLE 5 AB-Diblock MPC-HEMA Copolymer Formation via ATRP

[0177] 1 (2.0 g, 6.7 mmol) was polymerised in water (10 ml) as describedfor the homopolymerisation ([1]=17 wt. %, [I]=34 mM, theoretical Dp=20),but after 12 min (98% conversion) a degassed solution of HEMA(2-hydroxyethyl methacrylate) (0.88 g, 6.7 mmol) in methanol (5 ml) wasadded to give a reaction solution composition of 67:33 water:methanol([HEMA]=6 wt. %, [I]=23 mM, theoretical D_(p)=20). 1 h after theaddition of the second monomer the overall conversion for thepolymerisation had reached over 98%. The actual degree of polymerisationwas 19 for each block ((1), HEMA) as judged by ¹H NMR spectroscopy.

EXAMPLE 6 AB-Diblock MPC-HEMA Copolymer Formation via ATRP Directly in aH₂O:MeOH Solvent Mixture

[0178] Block copolymerisation of 1 with HEMA. 1 (4.1 g, 1.35×10⁻² mol)was polymerised first in 10.0 ml of a 50/50 vol/vol methanol/watermixture such that the molar ratios of [1]:[OEG-Br]:[CuCl]:[bipy] were10:1:1:2. After 150 min, the monomer conversion was 100%, and thehomopolymer obtained had a low polydispersity (Mw/Mn=1.19) with an Mn of3,000. HEMA (3.54 g, 2.7×10⁻² mol, target Dp=20), was then added to thepolymerising aqueous solution. After 24 h, a diblock copolymer wasobtained with essentially 100% monomer conversion. The copolymer Mn wascalculated by end-group analysis using ¹H NMR. GPC analysis was notpossible in this case because the copolymer formed micelles in water.

EXAMPLE 7 AB-Diblock MPC-OEGMA Copolymer Formation via ATRP

[0179] Another block copolymer was prepared in a similar fashion toExample 4, first 1 (2.0 g, 6.7 mmol) was polymerized in water (10 ml) asdescribed previously ([1]=17 wt. %, [I]=34 mM, theoretical D_(p)=20) andat 11 min (97% conversion) a degassed solution of OEGMA (oligoethyleneglycol methacrylate) (2.87 g, 6.7 mmol) in water (2 ml) was added([OEGMA]=19 wt. %, [I]=28 mM, theoretical D_(p)=20). 20 min after theaddition of the second monomer ¹H NMR spectroscopy was used to calculatean overall conversion of more than 98% for the diblock copolymer and adegree of polymerisation of 20 for each block. Aqueous GPC analysis gavean M_(n) of 8,750 and an M_(w)/M_(n) of 1.30 for homopolymer (1) and anM_(n) of 12,900 and an M_(w)/M_(n) of 1.34 for the diblock.

EXAMPLE 8 AB-Diblock OEGMA-MPC Copolymer Formation via ATRP

[0180] OEGMA (5.03 g, 1.2×10⁻² mol) was polymerised first in water (10ml) under the following conditions:[OEGMA]:[OEG-Br]:[CuCl]:[bipy]=20:1:1:2; target Dp=20. After 20 min, themonomer conversion reached 100% with Mn=8,600 and Mw/Mn=1.19, as judgedby aqueous GPC. 1 was then added as a solid (3.56 g, 1.2×10⁻² mol;target Dp=20) to the polymerising OEGMA solution. Essentially 100%monomer conversion was achieved after 60 min, as indicated by ¹H NMRspectroscopy (no residual vinyl double bonds). After clean-up andisolation, a diblock copolymer (Mn=15,000) was obtained with arelatively low polydispersity (Mw/Mn˜1.4).

EXAMPLE 9 AB-Diblock MPC-DMAPS Copolymer Formation via ATRP

[0181] 1 can also be block copolymerised with DMAPS([2-(Methacryloyloxy) ethyl] dimethyl (3-sulfopropyl) ammoniumhydroxide). 1 (4.0 g, 1.35×10⁻² mol) was homopolymerised first in water(10 ml); [1]:[OEG-Br]:[CuCl]:[bipy}=20:1:1:2, target Dp=20. After 120min, the monomer conversion was 100%, and the homopolymer obtained(Mn=6,200) had a low polydispersity (Mw/Mn=1.20). DMAPS monomer (3.8 g,1.35×10⁻² mol, target Dp=20) was then added to the polymerising aqueoussolution. After 21 h, a block copolymer with an Mn of 12,000 and apolydispersity of 1.27 was obtained.

EXAMPLES 10-15 AB-Diblock Copolymer Formulation with Other Com nomers

[0182] MPC was further polymerised using the general technique for ABblock copolymers with the conditions indicat d in Table 5 and withmonomers of varying hydrophobicity. The comonomer type, proportion andintended degree of polymerisation is shown in the table. The extent ofconversion after the specified reaction time as well as the measurednumber average molecular weight (by NMR) are also shown in the table.TABLE 3 Synthesis of MPC based diblock copolymers via statisticalpolymerisation ATRP [MPC] = 0.67M, [OEG-Br] = 0.067M, [CuBr] = 0.067M,[bipy] = 0.135M, MeOH = 10 ml, T = 20° C. MPC in copolymer Target TimeConversion Mn Mn Example # Comonomer (mol %) Dp (h) (%) (cal) (NMR) 10HEMA 10 10:90 6 >99 15000 13000 11 nBuMA 10 10:90 7 >99 16000 15000 12nBuMA 17 10:50 5 >99 10000 8500 13 HPMA 10 10:90 23 >99 16000 14000 14HPMA 17 10:50 21 >99 10000 9500 15 DHPMA 33 10:20 72 >99 6200 6000

EXAMPLES 16 TO 18 Further AB Block Synthesis in Water/Methanol Mixtures

[0183] Further examples of AB block copolymeriations of MPC as block Awere conducted using the ATRP method and under the general conditionsindicated in the heading to Table 4. The comonomers for the second blockand th relative levels, as well the solvent type the reaction times, theproduct and intermediate homopolymer characteristic and some of thepolydispersities are also shown in Table 4. TABLE 4 Synthesis of MPCbased diblock copolymers via ATRP [MPC] = 0.67M, [OEG-Br]:[CuCl]:[bipy]= 1:1:2, T = 20° C.; MPC polymerised first in all cases Time for 100%Conversion MPC in MPC Diblock Mn(AGPC) Mw/Mn copolymer Targethomopolymer copolymer MPC Diblock MPC Diblock comonomer (mol %) DpSolvent (mins) (h) homopolymer copolymer homopolymer copolymer DHPMA 3310:20 MeOH:H₂O 105 24 2900 — 1.18 1.43 (Ex 16) (50:50) HEMA 33 10:20MeOH:H₂O 150 24 3000 — 1.19 — (Ex 17) (50:50) DMAEMA 50 20:20 H₂O 100 205900 9000 1.20 1.42 (Ex 18)

EXAMPLE 19 ABC Triblock Copolymer of MPC and HEMA

[0184] A triblock copolymer was synthesised with MPC forming the first(A) and third (C) homopolymer blocks, using OEGBr as the initiator in a50:50 water:methanol solvent. MPC was used in an amount to give a targetDp for each block of 10. The monomer used to make homopolymer block Bwas 2-hydroxy ethylmethacrylate which was used in an amount to give atarget Dp of 20. It was found that about 100% conversion for the firstblock occurred in 1.5 hours, for the second in about 2.5 hours and forthe third in about 18.5 hours. The calculated Mn for A, AB and ABC wererespectively, 3000, 5600 and 8500, whilst the measured Mn values (byNMR) were 2900, 5500 and 8420.

EXAMPLES 20 AND 21 Oligomeric Difunctional Initiator

[0185] A difunctional inhibitor, a polypropylene oxide having twoterminal is bromine substituents (MW about 2000), was used to form twopolymers, each by carrying out a single step ATRP process with a singlemonomer, that is MPC (1), and using methanol as the solvent. The processwas conducted using 0.67M 1, 0.067 M CuCl transition metal compound,0.135 M bipyridine and sufficient initiator to provide a polymer with adegree of polymerisation of each block of MPC polymer of 10, for example20, and a degree of polymerisation of 20 for examples 21. The calculatedMn for the two examples were 7940 and 13900, respectively. The time forabout 100% conversions were, respectively 1.5 and 2 hours, whilst themeasured values of Mn were 7520 and 11600, respectively.

EXAMPLES 22-29

[0186] Table 6 describes the conditions and results for the synthesis ofa variety of MPC-DMAEMA and MPC-DEAEMA diblock copolymers by methanolicATRP. The reaction conditions were [MPC]=2.02M (6.0 g in 10 mlmethanol), [MPC]: [OEG-Br]:[CuBr]:[bipy]=30:1:1:2, T=20° C.; MPC waspolymerised first in all cases followed by neat DMAEMA (or DEAEMA).Almost complete monom r conversion was achieved after the time indicatedin Table 6 for the diblock, as indicated by ¹H NMR spectroscopy (noresidual vinyl double bonds). The reaction mixture was diluted withmethanol and passed through a silica column to remove residual ATRPcatalyst. After solvent evaporation, the products were dried undervacuum at room temperature. TABLE 6 Data of the polymerization of MPC -DMAEMA or DEAEMA diblock copolymers in methanol Time for >99% ConversionMPC in MPC MPC Mn(AGPC) Mw/Mn copolymer [Amine] HOMO Diblock MPC(a)MPC(b) MPC MPC Ex # Comonomer (mol %) TargetDp (M) (mins) (h) HOMODiblock HOMO Diblock 22 DEA 50 20:20 1.35 180 20 6200 14000 1.15 1.22 23DEA 33 10:20 1.35 180 21 3500 11000 1.17 1.29 24 DEA 50 30:30 2.02 13020 10000 21000 1.18 1.30 25 DEA 33 30:60 4.04 130 22 11000 31000 1.191.29 26 DEA 23 30:100 6.73 130 23 11000 43000 1.19 1.28 27 DMA 50 30:302.02 120 20 11000 22000 1.16 1.27 28 DMA 33 30:60 4.04 120 24 1000034000 1.15 1.29 29 DMA 23 30:100 6.73 120 48 11000 46000 1.18 1.32

EXAMPLE 30 Reversibl pH-Induced Micellisation for Polymer Exampl 24

[0187] Micelles with DEAEMA cores were obtained by careful adjustment ofthe solution pH. The MPC-DEAEMA diblock copolymers dissolved in diluteDCI or NaOD at 20° C. to produce a 1.0 w/v % copolymer solution with afinal pH of 1.37 and 8.68 respectively. FIG. 8 shows the proton NMRspectra obtained for the MPC-DEAEMA diblock copolymer at pH 1.37 and8.68 respectively.

[0188] Careful addition of dilute DCI to the MPC-DEAEMA diblockcopolymer solution produced a final pH of 1.37. Thus this copolymerdissolved molecularly in dilute aqueous solution at pH 1.37 and 20° C.,since both the MPC and DEAEMA blocks are hydrophilic under theseconditions. It can be characterised by proton NMR spectra in-FIG. 8a, inwhere the resonance at δ 1.25 and δ 3.4 ppm that was assigned to theresidual protons of DEA are presented.

[0189] Comparing FIG. 8, it is clear that the signals due to the DEAEMAresidues at δ 1.25 and δ 3.4 ppm have almost disappeared, indicatingmuch lower mobility and decreased solvation for this block. On the otherhand, the signals due to the MPC block at δ 4.0 and δ 3.5 ppm are stillprominent, indicating that this block forms the solvated micellarcorona. Micelles comprising DEAEMA cores and MPC corona were formed asexpected at pH 8.68 or higher.

[0190] Self-assembly was completely reversible: addition of acidresulted in instantaneous micellar dissolution.

EXAMPLE 31 MPC-Based Macromomer by (aq) ATRP Using a FunctionalInitiator

[0191] A two-neck round-bottom 100 ml flask was charged with vinylfunctional initiator 1 (shown in FIG. 9), Cu(I)Br and bipy. Water (10.0ml) was added and the mixture was stirred until a homogeneous solutionwas obtained. MPC monomer (2.0 g) was added to the reaction solution andthe flask was sealed with a rubber septum. The reaction mixture wasmaintained under dry nitrogen and at 20° C. for the duration of thepolymerisation. The molar ratio of [MPC]:[initiator]:[CuBr]:[bipy] usedin this case was 10:1:1:2, i.e. the target Dp was 10. TABLE 7 indicatesthe Mn and Mw values established for the reaction mixture after variousreaction periods and at completion of polymerisation Time Conv. Mn Mn No(min.) (%) (theory) (NMR) Mw/Mn 1 1 25 770 730 1.22 2 2 33 1000 960 1.233 5 39 1200 1100 1.23 4 10 54 1700 1600 1.24 5 30 81 2500 2100 1.25 6 6086 2900 2400 1.26 7 120 99 3100 2500 1.27

[0192]FIG. 9 shows the ¹H NMR spectra of the initiator, monomer used inthe project and the polymer obtained here. As can be seen from FIG. 10which shows the ¹Hnmr spectra during polymerisation, the area of thepolymer peak at δ1 ppm increased gradually with time while the peak areadue to the monomer vinyl signals at δ5.5-6.0 ppm decreased with time.The initiator's vinyl acetate peaks at δ5 and δ4.75 ppm due to CH₂═ andthe peaks at δ7.1 ppm correspond to ═CH—O— remained through thepolymerization process.

[0193] The aqueous GPC traces of the final polymer and intermediatepolymer obtained indicate the peaks corresponding to the polyMPC and thepeaks from residual MPC monomer. The monomer peak disappeared whenmonomer conversion reached over 99 percent, suggestion the completeconversion of the monomer.

EXAMPL 32 Polymerisation of a Statistical Quatro-Polymer via ATRP

[0194] An experimental procedure similar to that for Example 27 wasadopted, except that for the statistical quatro-polymerMPC_(0.30)nBuMA_(0.50)HPMA_(0.15)TMSPMA_(0.05) all of the monomers wereadded together at the beginning of the polymerization. TMSPMA istrimethoxysilylpropylmethacrylate. The concentration of MPC was 2.02Mand the ratios are given in moles. The concentration of OEG-Br was6.73×10⁻² and [OEG-Br]:[CuBr]: [bipy] is 1:1:2. Target Dp is 100. NMRafter completion of polymerisation indicated no residual comonomers(absence of vinyl signals between δ5.0-6.5 ppm). No GPC analysis waspossible with this copolymer due to the presence of the reactive silylgroups.

EXAMPLE 33 AB-Diblock MPC-DMAME Copolymer Formation via ATRP

[0195] MPC was block copolymerised with the methyl chloride quatemisedderivative of DMA (DMAME). MPC (6.0 g, 2.02×10⁻² mol) washomopolymerised first in a solvent mixture (2 ml methanol+8 ml water);[MPC]:[OEG-Br]:[CuBr]:[bipy]=30:1:1:2, target Dp=30. After 60 mins, themonomer conversion reached >99%, and the MPC homopolymer obtained had alow polydispersity (Mw/Mn<1.20). DMAME monomer (4.16 g, 2.02×10⁻² mol,target Dp=30) was then added to the polymerising solution. After 46 h, ablock copolymer with a monomer conversion of more than 99% was obtained,as indicated by ¹H NMR spectroscopy (no residual vinyl double bonds at δ5.5-6.0 ppm.

EXAMPLE 34 AB-Diblock MPC-DMABZ Copolymer Formation via ATRP

[0196] Another block copolymer was prepared in a similar fashion toExample 33, first MPC (6.0 g, 2.02×10⁻² mol)-was homopolymerised in10.00 ml of a 20/80 vol/vol methanovwater mixture such that the molarratios of [MPC]:[OEG-Br]:[CuBr]:[bipy] were 30:1:1:2 with a targetDp=30, at 60 mins (99% monomer conversion) a degassed benzyl chloridederivative of DMA [DMABZ] monomer (5.71 g, 2.02×10⁻² mol, target Dp=30)was then added to the polymerising aqueous solution. 50 hours after theaddition of the second monomer, ¹H NMR spectroscopy was used todetermine an overall conversion of more than 96% for the diblockcopolymer.

EXAMPLE 35 AB-Diblock PSSNa-MPC Copolymer Formation via ATRP

[0197] Sodium 4-styrenesulfonate (SSNa) was typically polymerised first,as follows: The SSNa monomer (4.17 g) was dissolved in a mixed solvent(15 ml H₂O+5 ml MeOH), the pH was adjusted to about 10-12 with NaOH andthe solution was degassed. The sodium 4-(bromomethyl)benzoate initiator(NaBMB) was added, together with the bipy ligand and Cu(I)Cl such thatthe [SSNa]:[NaBMB]:[CuCl]:[bipy] molar ratio was 50:1:1:2 and the targetDp was 50. After 120 mins, the SSNa monomer conversion reached 95% andthe second monomer, MPG, was then added as a solid (6.0 g, 2.02×10⁻²mol; target Dp=50) to the polymerising SSNa solution. More than 99% MPCconversion was achieved after 22 h, as indicated by ¹H NMR spectroscopy(no residual vinyl double bonds at δ 5.5-6.0 ppm).

EXAMPLE 36-37 AB-Diblock MPC-PPO Copolymer Formation via ATRP

[0198] Block copolymerisation of MPC was achieved using a poly(propyleneglycol) [PPO] macro-initiator: MPC (6.0 g, 2.02×10⁻² mol) waspolymerised in 10.0 ml methanol. The molar ratios of[MPC]:[PPO—Br]:[CuBr]:[bipy] were 30:1:1:2. After 12 h, the MPCconversion reached 100%,as indicated by ¹H NMR spectroscopy (no residualvinyl double bonds at δ 5.5-6.0 ppm).

[0199] Another MPC-PPO block copolymer was also synthesised with alonger MPC block under the following conditions: MPC (6.24 g, 2.10×10⁻²mol); [MPC]:[PPO—Br]:[CuCl];[bipy]=50:1:1:2.5. A diblock copolymer witha monomer conversion of 100% was obtained after 18 h.

EXAMPLE 38-43 MPC-Based Copolymers Formation via ATRP

[0200] Table 8 summarises the conditions and results from MPC diblockcopolymer syntheses. The f action conditions were [MPG]=2.02 M,[OEG-Br]:[CuBr]: [bipy]=1:1:2, T=20° C.; MPG was polymerised first inall cases. The second block was formed either of diethylaminoethylmethacrylate (DEA) or ammonium-2-sulphatoethylmethacrylate (SEM). TABLE8 Data for the MPC-based copolymers Time for >99% Conversion [Second MPCMPC Target Solvent Monomer] Homo Diblock Ex # Composition composition(mol dm⁻³) (mins) (h) 38 MPC₅₀ - DEA₅₀ MeOH 2.02 100 24 39 MPC₅₀ -DEA₁₀₀ MeOH 4.04 100 46 40 MPC₃₀ - DEA₄₀ MeOH 2.69 70 19 41 MPC₃₀ -DEA₅₀ MeOH 3.37 70 43 42 MPC₃₀ - DEA₇₀ MeOH 4.71 70 46 43 MPC₅₀ - SEM₅₀H₂O 2.02 40 24

EXAMPLE 44-47 Homopolymerisation of MPC in MeOH via ATRP Using NewFunctional Initiators and a PPO-Based Macro-Initiator

[0201] Table 9 describes the conditions and results from MPC homopolymersytheses. The reaction conditions were [MPC]=2.02×10⁻² mol (examples 44,46, 47), [MPC]=1.35×10⁻² mol (example 45), [OEG-Br]:[CuBr]:[bipy]=1:1:2,T=20° C. TABLE 9 Data for the MPC homopolymers Time for >99% Ex TargetSolvent [Initiator] Conversion # Composition composition (mol dm⁻³) (h)44 PEG₄₅ - MPC₄₀ MeOH 5.05 24 45 PEG₄₅ - MPC₁₀ MeOH 1.35 3 46 DMAEBr -MPC₂₀ MeOH 0.10 3 47 MEBr - MPC₅₀ MeOH 0.04 3

[0202] DMAEBr: This is a functional initiator for macromonomersyritheses. It was synthesised as follows:

[0203] MEBr: An NMR-labelled initiator. It was synthesised according to:

EXAMPLE 48 MPC-Based Macromonomer via ATRP

[0204]

[0205] The MPC polymer obtained in Example 46 was reacted with4-vinylbenzyl chloride [4-VBZCI] in methanol at 40° C. The vinylbenzylchloride quaterises the tertiary amine group at the terminal ofthe MPC polymer. The molar ratios of [MPC polymer]:[4-VBZCI] were 1:2. Amacromonomer was obtained after five days. This macromonomer wascontaminated with residual 4-VBZCI, as indicated by ¹H NMR spectroscopy.The peaks at δ 5.5-6.0 ppm and δ 6.5-7.0 ppm are due to the vinyl andaromatic groups of the 4-VBZCI, respectively. Therefore the resultingmacromonomer required further purification by washing with THF.

EXAMPL 49-50 A(BC)-Diblock MPC-MMA/DEA) Copolymer Formation via ATRP

[0206] MPC was block copolymerised with MMA/DEA. MPC (6.0 g, 2.02×10⁻²mol) was homopplymerised first in 10 ml methanol;[MPC]:[OEG-Br]:[CuBr]:[bipy]=30:1:1:2, target Dp=30. After 60 mins, themonomer conversion reached >99%, and the homopolymer obtained had a lowpolydispersity (Mw/Mn<1.20). MMA monomer (1.35 g, 1.35×10⁻² mol, target.Dp=20) and DEA monomer (5.0 g, 2.70×10⁻² mol, target Dp=40) was thenadded to the polymerising solution. After 24 h, a block copolymer with amonomer conversion of more than 99% was obtained; The reaction mixturewas diluted with methanol and passed through a silica column to removeresidual ATRP catalyst. After solvent evaporation, the products weredried under vacuum at room temperature. For-example 50, the MMA/DEAratio was changed to 40/20.

EXAMPLE 51 AB-Diblock MPC-HEMA Copolymer Formation via ATRP

[0207] Another block copolymer was prepared in a similar fashion toExample 49, first MPC (6.0 g, 2.02×10⁻² mol) was homopolymerised in10.00 ml of the methanol such that the molar ratios of[MPC]:[OEG-Br]:[CuBr]:[bipy] were 50:1:1:2 with target Dp=50. After 100mins (99% monomer conversion) a degassed HEMA monomer (2.1 g, 1.62×10⁻²mol, target Dp=40) was then added to the polymerising aqueous solution.20 hours after the addition of the second monomer, ¹H NMR spectroscopywas used to determine an overall conversion of more than 99% for thediblock copolymer. A white diblock copolymer (Mn=16,000) was obtainedwith a relatively low polydispersity (Mw/Mn˜1.25).

EXAMPLE 52 AB-Diblock MPC-CBMA Copolymer Formation via ATRP

[0208] MPC (6.0 g, 2.02×10⁻² mol) was polymerised first in methanol (10ml) under the following conditions:[MPC]:[OEG-Br]:[CuBr]:[bipy]=100:1:1:2; target Dp=100. After 120 mins,the monomer conversion reached almost 100% with Mn=31,000 andMw/Mn=1.16, as judged by aqueous GPC. The second monomer,N-methacryloyloxyethyl-N,Ndimethylammoniummethyl carboxylate inner saltCBMA (carboxybetaine methacrylate) was then added (4.82 g, 2.02×10⁻²mol; target Dp=100) to the polymerizing MPC solution.

[0209] Almost complete monomer conversion was achieved after 24 hours,as indicated by ¹H NMR spectroscopy (no residual vinyl double bonds). Awhite diblock copolymer (Mn=33,000) was obtained with a relatively lowpolydispersity (Mw/Mn˜1.20).

EXAMPLE 53 AB-Diblock MPC-MMA Copolymer Formation via ATRP

[0210] Block copolymerisation of MPC with MMA. MPC (6.0 g, 2.02×10⁻²mol, target Dp=100) was polymerised in 10.0 ml methanol. The molarratios of [MPC]:[OEG-Br]:[CuBr]:[bipy] were 100:1:1:2. After 3 hours,the monomer conversion reached more than 99%, as indicated by ¹H NMRspectroscopy (no residual vinyl double bonds at 65.5-6.0 ppm). MMAmonomer (0.6 g, 6.06×10 ⁻³ mol, target Dp=30) was then added to thepolymerising solution. After 24 h, a block copolymer with a monomerconversion of more than 99% is was obtained. The reaction mixture wasdiluted with methanol and passed through a silica column to removeresidual ATRP catalyst. After solvent evaporation, the products weredried under vacuum at room temperature.

EXAMPLES 54 AND 55 MPC-DMA-DEA ABC Triblock Copolymers Formation viaATRP

[0211] MPC (6.0 g, 2.02×10⁻² mol) was polymerised first in methanol (10ml) under the following conditions:[MPC]:[OEG-Br]:[CuBr]:[bipy]=30:1:1:2; target Dp=30. After 60 min, themonomer conversion reached 99% with Mn=10,000 and Mw/Mn=1.19, as judgedby aqueous GPC. The second monomer, DMA was then added as a liquid (2.15g, 1.35×10⁻² mol; target Dp=20) to the polymerising solution.Essentially 98% monomer conversion was achieved after 150 min, asindicated by ¹H NMR spectroscopy. DEA was then added as the thirdmonomer (5.05 g, 2.70×10⁻² mol, target Dp=40) to the polymerisingsolution. After 48 h, a block copolymer with an Mn of 20,000 and apolydispersity of 1.43 was obtained.

[0212] A MPC 30-DMA20-DEA. 30 triblock copolymer was polymerised usingthe same procedure with an appropriate adjustment to the level of DEA.

EXAMPLE 56 Polymerisation of an MPC-Vinylacetate Functional Macromonomer(Example 31)

[0213] The MPC-based macromer (0.5 g) described in example 31 wasdissolved in methanol (10 g) containing 0.5 wt % Perkadox 16 initiator.The solution was stirred at reflux for 4 hours after which the reactionmixture was allowed to cool. The solution was sampled and the solventremoved to yield a white solid. This was redissolved in D₂O andsubjected to ¹H NMR and compared to the spectrum of the macromer. Thepolymerised product showed no vinyl bonds at 5.5 and 6.0 ppm,demonstrating that the vinyl acetate reactive chain end group can bepolymerised to produce a comb-like poly-MPC polymer.

EXAMPLE 57 Shell-Crosslinking of MPC30-DMA20-DEA30

[0214] The a MPC30-DMA20-DEA30 triblock copolymer formed in Example 55was micellised as in Example 30. The intensity-average micelle diameterwas found to be 56 nm as a 1 wt. % aqueous solution at pH 9.6(polydispersity 0.064—which is good).

[0215] This was shell-crosslinked in solution by addition of1,2-bis(2-iodoethoxy)ethane (BIEE) at pH 8-9 for 3 days at 20° C. with aBIEE:DMA ratio 0.5 mol ratio (target crosslinking); this reacts toquatemise and cross-link the DMA residues. After shell-crosslinking ofthis triblock-copolymer, the micelles are 63 nm diameter (polydispersity0.08) at pH 9.6 and 67 nm (polydispersity 0.111) at pH 2.0. The lattermeasurement is a proof that the shell cross-linking was successful,since noncrosslinked micelles dissociate in acidic media.

EXAMPLE 58 Polymerisation of (MPC30-HPMA15-TMSPMA5)-(BMA50) Block QuatroPolymer

[0216] The polymer of (MPC30-HPMA1 5-TMSPMA5)-(BMA50) was made accordingto the process outlined in example 32, except the MPC, HPMA and TMSPMAwere added together and polymeris d statistically to 99% conversionbefore final addition of the BMA to form a separate block of hydrophobein the copolymer.

EXAMPLE 59 Drug Delivery Studies

[0217] Steel coupons coated with example 32 (statistical quatro polymer)and example 58 (block quatro polymer) and cured overnight at 70° C. Thecoupons were then immersed in a 10 mg/ml solution of dexamethasone ineither ethanol or ethanol:hexane (3:1) for 30 minutes. The-coupons wereremoved and allowed to air dry for a further 30 minutes before beingeluted into 5 ml of ethanol using sonication. The ethanol solution wasthen analysed by UV spectroscopy at 243 nm to detect the dexamethasoneeluant. FIG. 11 shows the relative amounts of drug loaded from the twosolutions using the two polymers. Loading from ethanol or ethanol:hexanehad no statistically significant difference on the total loading of drugin the statistical is quatro polymer (example 32). The was, however, asstatistically significant increase (p=0.04) for the block quatropolymer, indicating that the hexane co-solvent was able to access andswell the hydrophobic blocks and increase the drug loading relative tothe ethanol-swollen sample.

[0218] Similarly, when the same polymers were loaded from the mixedethanol:hexane solution and eluted in a kinetic experiment over 300minutes, a higher final absorbance was recorded for the block quatropolymer, indicating more effective loading into the polymer coating bythe solvent combination than for the statistical quatro-polymer coating(FIG. 12).

EXAMLE 60 Performance Data

[0219] Some of the polymers made above were subjected to tests todetermine whether they reduce the level of fibrinogen absorption. Thisis an indicator of haemocompatibility.

[0220] Fibrinogen ELISA was performed as previously described inWO-A-9301221. All polymers as indicated in Table 10 were dip-coated ontopolyethylene terephthalate (PET) strips (30 mm×10 mm) at 3 mm/sec fromethanolic solutions (10 mg/ml). The cross-linkable polymer (Example 32)was crosslinked at 70° C. overnight prior to testing. The positivecontrol coating was an MPC-laurylmethacrylate (1:2) copolymer made byconventional free radical polymerisation and described in WO-A-9301221and used commercially as a biocompatible and haemocompatible coatingwhich reduces the fibrinogen absorption. TABLE 10 Mean Abs @ % ExampleCoating 450 S.D. % CV Reduction t-Test 60.1.1 No coating 0.797 0.053 6.6— — 60.1.2 Control 0.136 0.012 8.9 83 0.000 60.1.3 Polymer 25 0.1160.015 11.6 85.5 0.000 60.1.4 Polymer 26 0.189 0.03 13.4 76.3 0.00060.2.1 No coating 0.909 0.117 12.9 — — 60.2.2 Control 0.175 0.021 1280.8 0.000 60.2.3 Polymer 32 0.19 0.028 14.8 79.1 0.000

[0221] These data indicate that the simple block copolymers of examples25 and 26 can be molecularly dissolved in an alcohol and physi-adsorbedonto planar surfaces to form stable biocompatible coatings. Thestatistical quatro polymer of example 32 can be coated and cured to forma stable biocompatible coating.

1. A polymerisation process in which ethylenically unsaturated monomersincluding a zwitterionic monomer of the general formula I Y B X  I inwhich Y is an ethylenically unsaturated group selected fromH₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A², R²O—CO—CR═CR—C—O,RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

A is —O— or NR¹; A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n)SO₃— in which n is 1 to 12; A² is selected from a bond, —O—, O—CO—,CO—O, CO—NR¹—, —NR¹—CO, O—CO—NR¹—, NR¹—CO—; R is hydrogen or C₁₋₄ alkyl;R¹ is hydrogen, C₁₋₄ alkyl or BX; R² is hydrogen or C₁₋₄ alkyl; B is abond, or a straight branched alkanediyl, alkylene oxaalkylene, oralkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; X is an ammonium phosphonium, or sulphoniumphosphate or phosphonate ester zwitterionic group. are polymerised by aliving radical polymerisation process in the presence of an initiator,and a catalyst.
 2. A polymerisation process according to claim in whichX is a group of the general formula II

in which the moieties A³ and A⁴, which are the same or different, are—O—, —S—, —NH— or a valence bond, preferably —O—, and We is a groupcomprising an ammonium, phosphonium or sulphonium cationic group and agroup linking the anionic and cationic moieties which is preferably aC₁₋₁₂-alkanediyl group, preferably in which W⁺ is a group of formula—W¹—N⁺R³ ₃, —W¹—P⁺R⁴ ₃, —W¹—S⁺R⁴ ₂ or —W¹-Het⁺ in which: W¹ isalkanediyl of 1 or more, preferably 2-6 carbon atoms optionallycontaining one or more ethylenically unsaturated double or triple bonds,disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, oralkylene is aryl alkylene, cycloalkanediyl, alkylene cycloalkyl,cycloalkyl alkylene or alkylene cycloalkyl alkylene, which group W¹optionally contains one or more fluorine substituents and/or one or morefunctional groups; and either the groups R³ are the same or differentand each is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl,or aryl, such as phenyl, or two of the groups R³ together with thenitrogen atom to which they are attached form an aliphatic heterocyclicring containing from 5 to 7 atoms, or the three groups R³ together withthe nitrogen atom to which they are attached form a fused ring structurecontaining from 5 to 7 atoms in each ring, and optionally one or more ofthe groups R³ is substituted by a hydrophilic functional group, and thegroups R⁴ are the same or different and each is R³ or a group OR³, whereR³ is as defined above; or Het is an aromatic nitrogen-, phosphorus- orsulphur-, preferably nitrogen-, containing ring, for example pyridine.3. A polymerisation process according to claim 2 in which X is a groupof general formula III

where the groups R⁵ are the same or different and each is hydrogen orC₁₋₄ alkyl, and m is from 1 to 4, in which preferably the groups R⁵ arethe same preferably methyl.
 4. A polymerisation process according toclaim 1 in which X is a group having the general formula IV

in which A⁵ is a valence bond, —O—, —S— or —NH—, preferably —O—; R⁶ is avalence bond (together with A⁵) or alkanediyl, —C(O)alkylene- or —C(O)NHalkylene preferably alkanediyl, and preferably containing from 1 to 6carbon atoms in the alkanediyl chain; W⁶ is S, PR⁷ or NR⁷; the or eachgroups R⁷ is hydrogen or alkyl of 1 to 4 carbon atoms or the two groupsR⁷ together with the heteroatom to which they are attached form aheterocyclic ring of 5 to 7 atoms; R⁸ is alkyanediyl of 1 to 20,preferably 1 to 10, more preferably 1 to 6 carbon atoms; A⁶ is a bond,NH, S or O, preferably O; and R⁹ is a hydroxyl, C₁₋₁₂ alkyl, C₁₋₁₂alkoxy, C₇₋₁₈ aralkyl, C₇₋₁₈-aralkoxy, C₆₋₁₈ aryl or C₆₋₁₈ aryloxygroup.
 5. A polymerisation process according to claim 4 in which A⁵ is abond; R⁶ is a C₂₋₆ alkanediyl; W² is NR⁷: each R⁷ is C₁₋₄ alkyl; R⁸ isC₂₋₆ alkanediyl; A⁶ is O; and R⁹ is C₁₋₄ alkoxy.
 6. A polymerisationprocess according to any preceding claim in which Y is H₂C═CR—CO—A— inwhich R is hydrogen or methyl and A is O.
 7. A polymerisation processaccording to any preceding claim in which B is a straight chainC₂₋₆-alkanediyl.
 8. A polymerisation process according to claim 1 inwhich the zwitterionic monomer is2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt.9. A polymerisation process according to any preceding claim in whichthe polymerisation mixture contains a non-polymerisable solvent,preferably in an amount, in the range of 10 to 500% by weight based onthe weight of ethylenically unsaturated monomer.
 10. A polymerisationprocess according to claim 9 in which the is solvent comprises water,preferably in an amount in the range 10 to 100% by weight based on theweight of ethylenically unsaturated monomer.
 11. A polymerisationprocess according to any preceding claim in which the ethylenicallyunsaturated monomer includes at least one comonomer, preferably selectedfrom anionic, cationic and non-ionic monomers, more preferablycomprising a non-ionic monomer.
 12. A polymerisation process accordingto claim 11 in which the comonomer is immiscible with the zwitterionicmonomer, and in which the polymerisation mixture comprises anon-polymerisable solvent in which both the zwitterionic monomer and thecomonomer are soluble.
 13. A polymerisation process according to claim12 in which the solvent includes water and a water-miscible organicsolvent, preferably a C₁₋₄ alkanol, more preferably methanol.
 14. Apolymerisation process according to any preceding claim which is an atomor group transfer radical polymerisation.
 15. A polymerisation processaccording to claim 14, in which the initiator has a radicallytransferable atom or group, and the catalyst comprises a transitionmetal compound and a ligand, in which the transition metal compound iscapable of participating in a redox cycle with the initiator and dormantpolymer chain, and the ligand is either any N-, O-, P- or S-containingcompound which can coordinate with the transition metal atom in aσ-bond, or any carbon-containing compound which can coordinate with thetransition metal in a π-bond, such that direct bonds between thetransition metal and growing polymer radicals and not formed.
 16. Apolymerisation process according to claim 15 in which the initiator isof the general formula V R¹¹R¹²R¹³C—X²  V where: X² is selected from thegroup consisting of Cl, Br, I, OR¹⁰, SR¹⁴, SeR¹⁴, OP(═O)R¹⁴,OP(═O)(OR⁴)₂, O—N(R¹⁴)₂ and S—C(═S)N(R¹⁴)₂, where R¹⁰ is alkyl of from 1to 20 carbon atoms in which each of the hydrogen atoms may beindependently replaced by halide, R¹⁴ is aryl or a straight or branchedC₁-C₂₀ alkyl group, and where an N(R¹⁴)₂ group is present, the two R¹⁴groups may be joined to form a 5 or 6-membered heterocyclic ring; andR¹¹, R¹² and R¹³ are each independently selected from the groupconsisting of H, halogen, C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl, C(═O)R¹⁵,C(═O)NR¹⁶R¹⁷, COCl, OH, CN, C₂-C-₂₀ alkenyl, C₂-C₂₀ alkenyl oxiranyl,glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, C₁₋-C₆ alkyl in whichfrom 1 to all of the hydrogen atoms.are replaced with halogen, and C₁-C₆alkyl substituted with from 1 to 3 substituents selected from the groupconsisting of C₁-C₄ alkoxy, aryl, heterocyclyl, C(═O)R¹⁵, C(═O)NR¹⁶R¹⁷,—CR¹²R¹³X², oxiranyl and glycidyl; where R¹⁵ is alkyl of from 1 to 20carbon atoms, alkoxy of from 1 to 20 carbon atoms, oligo(alkoxy) inwhich each alkoxy group has 1 to 3 carbon atoms, aryloxy orheterocyclyloxy any of which groups may have substituents selected fromoptionally substituted alkoxy, oligoalkoxy, amino (including mono- anddi-alkyl amino and trialkyl ammonium, which alkyl groups, in turn mayhave substituents selected from acyl, alkoxycarbonyl, alkenoxycarbonyl,aryl and hydroxy) and hydroxyl groups; and R¹⁶ and R¹⁷ are independentlyH or alkyl of from 1 to 20 carbon atoms which alkyl groups, in turn mayhave substiuents selected from acyl, alkoxycarbonyl, alkenoxycarbonyl,aryl and hydroxy, or R¹⁶ and R¹⁷ may be joined together to form analkanediyl group of from 2 to 5 carbon atoms, thus forming a 3- to6-membered ring; such that not more than two of R¹¹, R¹² and R¹³ are H.17. The process of claim 16, wherein no more than one of R¹¹, R¹² andR¹³ is H.
 18. A polymerisation process according to claim 16 in which x²is selected from Cl, Br or I, preferably Br.
 19. A polymerisationprocess according to any of claims 16 to 18 in which R¹¹ and R¹² areeach methyl and R¹³ is —CO—R¹⁵ in which R¹⁵ is oligoalkoxy, preferablymethoxy-oligoethoxy in which there are 2 to 10 ethoxy groups.
 20. Apolymerisation process according to any of claims 15 to 19 in which thetransition metal compound M_(t) ^(n+)X′_(n), where: M_(t) ^(n+) may beselected from the group consisting of Cu¹⁺, Cu²⁺, Fe²⁺, Fe³⁺, Ru²⁺, Ru⁺,Cr²⁺, Cr³⁺, Mo²⁺, Mo³⁺, W²⁺, V³⁺, Mn²⁺, Mn³⁺, Mn⁴⁺, Rh³⁺, Rh⁴⁺, Re²⁺,Re³⁺,Co⁺, Co²⁺, Co³⁺, V²⁺, V³⁺, Zn⁺, Zn²⁺, Ni²⁺, Ni³⁺, Au⁺, Au²⁺, Ag⁺and Ag²⁺; X′ is selected from the group consisting of halogen,C₁₂-C₆-alkoxy, (SO₄)_(1/2), (PO₄)_(1/3), (R¹⁸PO₄)_(1/2) (R¹⁸ ₂PO₄),triflate, hexafluorophosphate, methanesulphonate, arylsulphonate, CN andR¹⁹CO₂, where R¹⁸ is aryl or a straight or branched C₁₋₂₀ alkyl and R¹⁹is H or a straight or branched C₁-C₆ alkyl group which may besubstituted from 1 to 5 times with a halogen; and n is the formal chargeon the metal (0≦n≦7).
 21. A polymerisation process according to claim 20in which the metal compound is CuHal or RuHal₂ where Hal is chlorine orbromine.
 22. A polymerisation process according to any of claims 15 to20, wherein said ligand is selected-from the group consisting of a)compounds of the formulas: R²⁰-Z-R²¹ and R²⁰-Z-(R²²-Z)_(m)—R²¹ where:R²⁰ and R²¹ are independently selected from the group consisting of H,C₁-C₂₀ alkyl, aryl, heterocyclyl and C₁-C₆ alkoxy, C₁-C₄ dialkylamino,C(═O)R²², C(═O)R²³R²⁴ and A⁷C(═O)R²⁵, where A⁷ may be NR²⁶ or O; R²² isalkyl of from 1 to 20 carbon atoms, aryloxy or heterocyclyloxy; R²³ andR²⁴ are independently H or alkyl of from 1 to 20 carbon atoms or R²³ andR²⁴ may be joined together to form an-alkanediyl group of from 2 to 5carbon atoms, thus forming a 3 to 6-membered ring; R²⁵ is H, straight orbranched C₁-C₂₀ alkyl or aryl and R²⁶ is hydrogen, straight or branched;C₁₋₂₀-alkyl or aryl; or R²⁰ and R²¹ may be joined to form together withZ, a saturated or unsaturated ring; Z is O, S, NR²⁷ or PR²⁷, where R²⁷is selected from the same group as R²⁰ and R²¹, and where Z is PR²⁷, R²⁷can also C₁-C₂₀ alkoxy or Z may be a bond CH₂ or a fused ring, where oneor both of R²⁰ and R²³ is heterocyclyl, each R²² is independently adivalent group selected from the group consisting of C₁-C₈cycloalkanediyl, C₁-C₈ cycloalkenediyl, arenediyl and heterocyclylenewhere the covalent bonds to each Z are at vicinal positions or R²² maybe joined to one or both of R²⁰ and R²¹ to formulate a heterocyclic ringsystem; and m is from 1 to 6; b) CO; c) porphyrins and porphycenes,which may be substituted with from 1 to 6 halogen atoms, C₁₋₆ alkylgroups, C₁₋₆-alkoxy groups, C₁₋₆ alkoxycarbonyl, aryl groups,heterocyclyl groups, and C₁₋₆ alkyl groups further substituted with from1 to 3 halogens; d) compounds of the formula R²³R²⁴C(C(═O)R²⁵)₂, whereR^(25 is) C₁₋₂₀ alkyl, C₁₋₂₀ alkoxy, aryloxy or heterocyclyloxy; andeach of R²³ and R²⁴ is independently selected from the group consistingof H, halogen, C₁₋₂₀ alkyl, aryl and heterocyclyl, and R²³ and R²⁴ maybe joined to form a C₁₋₈ cycloalkyl ring or a hydrogenated aromatic orheterocyclic ring, of which the ring atoms may be further substitutedwith 1 to 5 C₁₋₆alkyl groups, C₁₋₆ alkoxy groups, halogen atoms, arylgroups, or combinations thereof; and e) arenes and cyclopentadienylligands, where said cyclopentadienyl ligand may be substituted with fromone to five methyl groups, or may be linked through and ethylene orpropylene chain to a second cyclopentadienyl ligand.
 23. Apolymerisation process according to claim 22 in which the ligand isbipyridine, triphenylphosphine, 1,1,4,7,10,10-hexamethyl-triethylenetetramine, or

where R is an alkyl or substituted alkyl group, in which the substituentis selected from amino, including alkylamino and acylamino, alkoxy,hydroxy, acyl, acyloxy, alkoxycarbonyl, heterocyclyl, ionic, and halogensubstituents.
 24. A polymerisation process according to any precedingclaim in which the molar ratio of initiator to ethylenically unsaturatedmonomer is an the range 1:(5 to 500), preferably 1:(10 to 100).
 25. Apolymerisation process according to any preceding claim in which thepolymer product has an average degree of polymerisation in the range 5to 500, preferably 10 to
 100. 26. A polymerisation process according toany preceding claim in which the polydispersity of the polymer productis less than 1.5.
 27. A polymerisation process according to anypreceding claim which is carried out until the level of residualethylenically unsaturated monomer is less than 5%.
 28. A polymerisationprocess according to claim 27 in which th initial polymer product issubjected to a second step of living radial polymerisation in whichfurther ethylenically unsaturated monomer is contacted with the initialpolymer product which acts as initiator in the presence of a catalyst,to form a block copolymer product.
 29. A polymerisation processaccording to claim 28 in which the initial polymer product is notisolated from the product mixture before the second step.
 30. Apolymerisation process according to claim 29 in which the furthermonomers are added to the product mixture of the first step-as asolution in a solvent which is miscible with the said product mixture.31. A polymerisation process according to claim 28 in which the initialpolymer product is isolated from the catalyst of the first step, and inwhich a different catalyst is used in the second step, the catalystpreferably being as defined in claim
 15. 32. A polymerisation processaccording to claim 28 or claim 31 which the first polymerisation isconducted in the presence of a non-polymerisable solvent and in whichthe initial polymer product is isolated from the solvent, and in whichthe second step is conducted in the absence of a non-polymerisablesolvent or in the presence of a non-polymerisable solvent different fromor the same as the solvent used in the first step.
 33. A polymer formedfrom ethylenically unsaturated monomers including a zwitterionic monomerof the general formula I Y B X  I in which Y is an ethylenicallyunsaturated group selected from H₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—,H₂C═CR—CH₂A², R²O—CO—CR═CR—CO—O, RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n) SO₃— in which n is1 to 12; A is —O— or NR¹; A² is selected from a bond —O—, O—CO—, CO—O,CO—NR¹—, —NR¹—CO, O—CO—NR¹—, NR¹—CO—O—; R is hydrogen or C₁₋₄ alkyl; R¹is hydrogen, C₁₋₄ alkyl or BX; R² is hydrogen or C₁₋₄ alkyl; B is abond, or a straight branched alkanediyl, alkylene oxaalkylene, oralkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; X is an ammonium, phosphonium, or sulphoniumphosphate or phosphonate ester zwitterionic group, having a degree ofpolymerisation in the range 5 to 500 and a polydispersity of less than1.5.
 34. A polymer according to claim 33 in which the zwitterionicmonomer is as defined in any of claims 2 to
 8. 35. A polymer accordingto claim 33 or claim 34 in which the ethylenically unsaturated monomerincludes at least one comonomer selected from anionic, cationic andnon-ionic monomers, preferably comprising a non-ionic monomer.
 36. Apolymer according to any of claims 33 to 35 in which the ethylenicallyunsaturated monomer includes at least one cross-linkable monomer,preferably a monomer comprising a reactive silyl group, more preferablya trialkoxysilylalkyl(alk)acrylate.
 37. A polymer according to claim 33having at least one termirial group or atom which is transferable toproduce a radical in the presence of a catalyst which comprises atransition metal compound and a ligand, in which the transition metalcompound is capable of participating in a redox cycle with the initiatorand dormant polymer chain, and the ligand is either any N-, O-, P- orS-containing compound which can coordinate with the transition metalatom in a σ-bond, or any carbon-containing compound which can coordinatewith the transition metal in a π-bond, such that direct bonds betweenthe transition metal and molecules of the polymer are not form d.
 38. Apolymer according to claim 37 in which the said terminal atom or groupis a halogen atom, preferably a chlorine, or more preferably, a bromineatom.
 39. A polymer according to claim 37 or 38 which has one suchterminal group and, at the other end of the polymer chain, has anoligo(alkoxy)alkyl group joined to the end residue derived from the saidethylenically unsaturated monomers.
 40. A polymer according to claim 37or claim 38 which has one such terminal group and, at the other end ofthe polymer chain has a functional group joined to the end residuederived from said ethylenically unsaturated monomers.
 41. A polymeraccording to claim 40 in which the functional group comprises anethylenically unsaturated group and/or a tertiary or quaternary aminegroup.
 42. A block copolymer of the A-B or A-B-A type in which A and Bare the same or, preferably, different, in which at least one of the Aand B is formed from ethylenically unsaturated monomer including azwitterionic monomer of the general formula VI Y B X′  VI in which Y isan ethylenically unsaturated group selected from H₂C═CR—CO—A—,H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A², R²O—CO—CR═CR—CO—O, RCH═CH—CO—O—,RCH═C(COOR²)CH₂—CO—O,

A is —O— or NR¹; A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n)SO₃— in which n is 1 to 12; A² is select d from a bond —O—, O—CO—, CO—O,CO—NR¹—, —NR¹—CO, O—CO—NR¹—, NR¹—CO—O—; R is hydrogen or C₁₋₄ alkyl; R¹is hydrogen, C₁₋₄ alkyl or BX: R² is hydrogen or C₁₋₄ alkyl; B is abond, or a straight branched alkanediyl, alkylene oxaalkylene, oralkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; and X¹ is a zwitterionic group.
 43. A blockcopolymer according to claim 42 in which the zwitterionic group is anammonium, sulphonium or phosphonium phosphate or phosphonate esterzwitterionic group.
 44. A block copolymer according to claim 42 or 43 inwhich the zwitterionic monomer has the further features as defined inany of claims 2 to
 8. 45. A block copolymer according to any of claims42 to 44 in which the block comprising zwitterionic monomer is formedfrom ethylenically unsaturated monomers comprising at least onecomonomer selected from cationic, anionic and non-ionic monomers.
 46. Ablock copolymer according to any of claims 42 to 44 in which the degreeof polymerisation of the block comprising zwitterionic monomer is in therange 2 to 100, preferably 5 to
 50. 47. A block copolymer according toany of claims 42 to 46 in which both blocks A and B are formed fromethylenically unsaturated monomer, the monomers from which A is formedcomprising either different monomers to the monomers from which B isformed, or the same monomers as the monomers from which B is formed butin different ratios.
 48. A block copolymer according to claim 47 inwhich one of the blocks is formed from monomers comprising anoligoalkoxy monomer of the general formula VII Y¹(R²⁶O)_(p)R²⁷  VII inwhich Y¹ is an ethylenically unsaturated group selected fromH₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—, H₂C═CR—CH₂A², R²O—CO—CR═CR—CO—O,RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

A is —O— or NR¹; A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n)SO₃— in which n is 1 to 12; A² is selected from a bond —O—, O—CO—, CO—O,CO—NR¹—, —NR¹—CO, O—CO—NR¹—, NR¹—CO—O—; R is hydrogen or C₁₋₄ alkyl; R¹is hydrogen, C₁₋₄ alkyl or BX; R² is hydrogen or C₁₋₄ alkyl; and R²⁶ isC₂₋₃ alkanediyl; R²⁷ is C₁₋₁₂ alkyl, C₇₋₁₂ aralkyl or aryl; and p is 1to
 50. 49. A block copolymer according to claim 48 in which Y¹ isH₂C═CR—CO—A— in which R is methyl and A is O.
 50. A block copolymeraccording to claim 47 in which the monomers from which A is formedinclude a first zwitterionic monomer of the formula VI and the monomersfrom which B is formed include a second zwitterionic monomer of theformula VI different from the first zwitterionic monomer.
 51. A polymerof the formula VIII

in which X² is selected from the group consisting of Cl, Br, I, OR¹⁰,SR¹⁴, SeR¹⁴, OP(═O)R¹⁴, OP(═O)(OR¹⁴)₂, O—N(R¹⁴)₂ and S—C(═S)N(R¹⁴)₂,where R¹⁰ is alkyl of from 1 to 20 carbon atoms in which each of thehydrogen atoms may be independently replaced by halide, R¹⁴ is aryl or astraight or branched C₁-C₂₀ alkyl group, and where an N(R¹⁴)₂ group ispresent, the two R¹⁴ groups may be joined to form a 5- or 6-memberedheterocyclic ring; and R¹¹, R¹² and R¹³ are each independently selectedfrom the group consisting of H, halogen, C₁-C₂₀ alkyl, C₃-C₈ cycloalkyl,C(═O)R¹⁵, C(═O)NR¹⁶R¹⁷, COCl, OH, CN, C₂-C₂₀ alkenyl, C₂-C₂₀ alkenyloxiranyl, glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, C₁₋-C₆ alkylin which from 1 to all of the hydrogen atoms are replaced with halogen,C₁-C₆ alkyl substituted with from 1 to 3 substituents selected from thegroup consisting of C₁-C₄ alkoxy, aryl, heterocyclyl, C(═O)R¹⁵,C(═R)NR¹⁶R¹¹, —CR¹²R¹³X, oxiranyl and glycidyl; where R¹⁵ is alkyl offrom 1 to 20 carbon atoms, alkoxy of from 1 to 20 carbon atoms,oligo(alkoxy) in which each alkoxy group has 1 to 5 carbon atoms,aryloxy or heterocyclyloxy any of which groups may have substituentsselected from optionally substituted alkoxy, oligoalkoxy, amino(including mono- and di-alkyl amino and trialkyl ammonium, which alkylgroups, in turn may have substiuents selected from acyl, alkoxycarbonyl,alkenoxycarbonyl, aryl and hydroxy) and hydroxyl groups; and R¹⁶ and R¹⁷are independently H or alkyl of from 1 to 20 carbon atoms which alkylgroups, in turn may have substiuents selected from acyl, alkoxycarbonyl,alkenoxycarbonyl, aryl and hydroxy, or R¹⁶ and R¹⁷ may be joinedtogether to form an alkylene group of from 2 to 5 carbon atoms, thusforming a 3- to 6-membered ring; such that not more than two of R¹¹, R¹²and R¹³ are H M¹ is the residue of a zwitterionic monomer zwitterionicmonomer of the general formula I Y B X  I in which Y is an ethylenicallyunsaturated group selected from H₂C═CR—CO—A—, H₂C═CR—C₆H₄—A¹—,H₂C═CR—CH₂A², R²O—CO—CR═CR—CO—O, RCH═CH—CO—O—, RCH═C(COOR²)CH₂—CO—O,

A is —O— or NR¹; A¹ is selected from a bond, (CH₂)_(n)A² and (CH₂)_(n)SO₃— in which n is 1 to 12; A² is selected from a bond —O—, O—CO—, CO—O,CO—NR¹—, —NR¹—CO, O—CO—NR¹—, NR¹—CO—O—; R is hydrogen or C₁₋₄ alkyl; R¹is hydrogen, C₁₋₄ alkyl or BX; R² is hydrogen or C₁₋₄ alkyl; B is abond, or a straight branched alkanediyl, alkylene oxaalkylene, oralkylene (oligooxalkylene) group, optionally containing one or morefluorine substituents; X is an ammonium, phosphonium, or sulphoniumphosphate or phosphonate ester zwitterionic group; x is 2 to 500; M² isthe residue of an ethylenically unsaturated comonomer polymerisable withthe zwitterionic monomer; and y is 0 to
 500. 52. A polymer according toclaim 51 in which Ml has the formula IX

in which R²⁷ is selected from hydrogen C₁₋₄ alkyl and groups CO OR² inwhich R² is hydrogen or C₁₋₄ alkyl; R²⁸ is selected from hydrogen andC₁₋₄ alkyl; R²⁹ is selected from hydrogen, C₁₋₄ alkyl and groups CO OR2,provided that R²⁷ and R²⁹ are not both CO OR²; R³⁰ is selected from abond, a group CH₂A², in which A² is selected from a bond, —O—, —O—CO—,—CO—O—, —CO—NR¹—, —NR¹—CO—, —O—CO—NR¹— and —NR¹—CO—O, a group —COA— inwhich A is —O— or NR¹, in which R¹ is hydrogen or C₁₋₄ alkyl or BX, anda group —C₆H₄—A¹— in which A¹ is (CH₂)_(n)A², a bond or (CH₂)_(n) SO₃,or R³⁰ and R²⁸ or R³⁰ and R²¹ may be joined to form a group

where the N atom is joined to B; and B and X are as defined in claim 51.53. A polymer according to claims 51 or claim 52 and 49 in which x is 5to
 50. 54. A polymer according to any of claims 51 to 53 in which thecomonomer has the general formula X

in which R³¹ is selected from hydrogen, halogen, C₁₋₄ alkyl and groupsCOOR² in which R² is hydrogen and C₁₋₄ alkyl; R³² is selected fromhydrogen, halogen and C₁₋₄ alkyl; R³³ is selected from hydrogen,halogen, C₁₋₄ alkyl and groups COOR² provided that R³¹ and R³³ are notboth COOR²; and R³⁴ is a C₁₋₁₀ alkyl, a C₁₋₂₀ alkoxycarbonyl, a mono-ordi-C₁₋₂₀ alkyl) amino carbonyl, a C₆₋₂₀ aryl (including alkaryl), aC₇₋₂₀ aralkyl, a C₆₋₂₀ aryloxycarbonyl, a C₁₋₂₀-aralkyloxycarbonyl, aC₆₋₂₀ arylamino carbonyl, a C₇₋₂₀ aralkyl-amino, a hydroxyl or a C₂₋₁₀acyloxy group, any of which may have one or more substituents selectedfrom halogen atoms, alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino,amine (including mono and di-alkyl amino and trialkylammonium in whichthe alkyl groups may be substituted), carboxyl, sulphonyl, phosphoryl,phosphino, (including mono- and di-alkyl phosphine andtri-alkylphosphonium), zwitterionic, hydroxyl, vinyloxycarbonyl andother vinylic or allylic, and reactive silyl or silyloxy groups, such astrialkoxysilyl groups; or R³⁴ and R³³ or R³⁴ and R³² may together form—CONR³⁵CO in which R³⁵ is a C₁₋₂₀ alkyl group.
 55. A polymer accordingto claim 54 in which R³¹ and R³² are hydrogen, R³³ is methyl and R³⁴ isa C₁₋₂₀ alkoxycarbonyl, optionally having a hydroxy substituent.
 56. Apolymer according to any of claims 51 to 55 in which X² is bromine, R¹¹and R¹² are each methyl and R¹³ is CO R¹⁵ in which R¹⁵ is oligoalkoxy,preferably methoxy-oligoethoxy in which there are 2 to 10 ethoxy groups.57. A block copolymerisation process in which ethylenically unsaturatedmonomers are polymerised in the presence of, as initiator, a polymeraccording to any of claims 51 to 56 and a catalyst.
 58. A blockcopolymerisation process according to claim 57 in which the catalyst isas defined in claim
 15. 59. A block copolymerisation process accordingto claim 58 in which the catalyst is as defined in any of claims 20 to23.
 60. A block copolymerisation process according to any of claims 57to 59 in which the molar ratio of polymer-initiator to ethylenicallyunsaturated monomer is in the range 1:(2 to 500), preferably 1:(10 to50).
 61. A macromonomer which is a polymer according to claim 33 havinga terminal group comprising an ethylenically unsaturated group.
 62. Apolymer formed by polymerising by radical polymerisation ethylenicallyunsaturated monomers including a macromonomer according to claim 61 or apolymer according to claim 41 in which the said functional groupcomprises an ethylenically unsaturated group.
 63. A cross-linked polymerformed by subjecting a polymer according to claim 36 to conditions underwhich the cross-linkable groups react to cross-link the polym r.
 64. Useof a block copolymer according to any of claims 42 to 50 as a drugdelivery matrix.
 65. A composition comprising a block copolymeraccording to any of claims 42 to 50 and, absorbed in the copolymer, adrug capable of being released from the copolymer.
 66. A compositionaccording claim 65 in which the block copolymer is in the form of afilm.
 67. A composition according to claim 65 in which the blockcopolymer is in the form of a dispersion of micelles in an aqueouscontinuous phase.
 68. A pharmaceutical composition comprising a blockcopolymer according to any of claims 42 to 50 and, absorbed in thecopolymer, a drug capable of being released from-the copolymer and apharmaceutical excipient.